Substituted benzofurans, benzothiophenes, benzoselenophenes and indoles and their use as tubulin polymerisation inhibitors

ABSTRACT

The present invention relates generally to substituted benzofurans, benzothiophenes, and indoles and their use as tubulin polymerization inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/461,213, filed onMay 1, 2012 (now allowed), which is a continuation of U.S. Ser. No.12/162,917, filed May 28, 2009 (now U.S. Pat. No. 8,198,466, granted onJun. 12, 2012) as the United States national stage application ofInternational Application No. PCT/AU2007/000101, filed Feb. 2, 2007,which claims the benefit of U.S. Provisional Application No. 60/765,337,filed Feb. 3, 2006, the entire disclosures of each of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to chemical compounds andmethods for their use and preparation. In particular, the inventionrelates to chemical compounds which may possess useful therapeuticactivity, use of these compounds in methods of therapy and themanufacture of medicaments as well as compositions containing thesecompounds.

BACKGROUND OF THE INVENTION

Tubulin is an important target in controlling disease states associatedwith cell proliferation such as cancer and inflammation (eg, psoriasis).Tubulin is composed of a heterodimer of two related proteins called αand β tubulin. Tubulin polymerises to form structures calledmicrotubules. Compounds that inhibit tubulin's ability to polymerise toform microtubules interrupt cell division which is dependent on theformation of microtubules to form mitotic spindles. Examples of suchcompounds include the Vinca alkaloids such as vincristine andvinblastine.

Furthermore, compounds that inhibit the depolymerisation of microtubulescan also prevent cell division since they often disrupt the properformation of mitotic spindles which must also disassemble in order forcell division to be completed. Interruption of the mitotic process inthis manner often induces cell death by an apoptotic mechanism. Examplesof compounds which act in this manner include the taxoids such aspaclitaxel.

For these antimitotic agents, selectivity for diseased versusnon-diseased tissue is based on relative rates of proliferation, wherethe diseased tissue more rapidly proliferates. Accordingly, diseasedtissue is generally more sensitive to the effect of these agents becauseit is more likely to be in a state of mitosis which is the stage of acell's life cycle affected by agents that target tubulin. Unfortunatelyhowever, a number of normal, healthy tissues also have quite high ratesof proliferation (for example hair follicles and the lining of thegastro-intestinal tract) and accordingly, these tissues can be damagedduring chemotherapy with these agents.

Tubulin is also a target for treating disease states that are dependentor result from the abnormal formation of blood vessels(neovascularisation) such as in cancerous tumours and in ocularmyopathy. In these cases the cytoskeleton of the vascular endothelialcells are disrupted through depolymerisation of microtubles, whichresults from inhibiting the polymerisation of tubulin to formmicrotubules. Microtubule length is dependent on the rate ofdepolymerisation versus polymerisation. Depolymerising microtublesthrough inhibition of polymerisation leads to a change in endothelialcell morphology, which then causes a blockage or shutdown in blood flow.In the case of cancerous tumours, blood flow to the diseased tissue isstopped, depriving the tumour of oxygen and nutrients leading tonecrotic cell death. Neovascular systems are more sensitive to theseagents because they are more dependent on microtubule cytoskeletons thannormal, healthy, vascular endothelial cells which are also supported byactin based cytoskeletal structures. For a number of tubulinpolymerisation inhibitors (TPIs) that target the colchicine binding siteof tubulin, the vascular targeting modality can be achieved at a lowerin vivo concentration than the antiproliferative modality. In theorythough, agents that target the colchicine binding domain of tubulin arepotentially dual mode agents (ie. antimitotic and antivascular).

One of the most potent inhibitors of tubulin polymerisation that bindsto the colchicine binding domain of tubulin is the cis-stilbene,combretastatin A4 (CA4) (1). Due to its insolubility CA4 is administeredas its prodrug equivalent combretastatin A4 disodium phosphate (CA4P)(2), where the phosphate is rapidly cleaved in vivo. CA4P is currentlyundergoing phase I and II clinical trials and is the most advancedvascular targeting agent being trialed. In view of some of thedraw-backs associated with CA4P, such as, instability (can isomerise tothe inactive trans-stilbene), toxicity and rapid clearance, a number ofsynthetic groups have sought to prepare more stable analogues that couldbe designed to exhibit an improved therapeutic index and exhibitimproved pharmacokinetics. Recently, a number of TPIs have beenidentified that contain the benzofuran, indole or benzothiophene ringsystems (see for example, WO 1998/39323, WO 2001/19794 and WO2001/68654) or chromene and dihydronapthalene ring systems (see forexample, WO 2005/113532, and WO 1998/39323). Such ring systems are quitestable and should over come the stability issues associated with CA4P.Unfortunately, such compounds only exhibit moderate tubulin binding andanti-mitotic activity. Accordingly, there exists a need to identifyother compounds which are more stable than CA4 and exhibit satisfactorypharmacological properties and/or activity.

SUMMARY

The present invention provides compounds of formula (I) and saltsthereof;

wherein;

X represents O, S, SO, SO₂, Se, SeO, SeO₂ or NR where R is selected fromH, O, optionally substituted acyl, optionally substituted alkenyl,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, andoptionally substituted sulfonyl;

R^(1A) and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl;

R^(1C) represents C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylamino, or C₁₋₃dialkylamino;

R^(1D) represents hydroxy or amino;

L represents C═O, O, S, SO, SO₂, Se, SeO, SeO₂, C═NZ′, or NR′ where Z′is H, optionally substituted alkyl, optionally substituted aryl oroptionally substituted amino; and where R′ is selected from H, O,optionally substituted acyl, optionally substituted alkenyl, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedcycloalkenyl, optionally substituted cycloalkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted sulfonyl;

R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and

Q represents H, CN, halogen, trialkylsilyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted acyl, optionally substituted oxyacyl, optionallysubstituted acylamino, optionally substituted aminoacylamino, OR″, SR″or NR″R″, where each R″ independently represents, H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedacyl and optionally substituted oxyacyl, or NR′″NR″, where each R′″independently represents H, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl and optionally substituted heteroaryl.

The present invention also provides a method for treating a diseasestate by inhibiting tubulin polymerisation including the step ofadministering to a patient in need thereof a compound of formula (I) ora pharmaceutically acceptable salt thereof;

wherein;

X represents O, S, SO, SO₂, Se, SeO, SeO₂ or NR where R is selected fromH, O, optionally substituted acyl, optionally substituted alkenyl,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, andoptionally substituted sulfonyl;

R^(1A) and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl;

R^(1C) represents C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylamino, or C₁₋₃dialkylamino;

R^(1D) represents hydroxy or amino;

L represents C═O, O, S, SO, SO₂, Se, SeO, SeO₂, C═NZ′, or NR′ where Z′is H, optionally substituted alkyl, optionally substituted aryl oroptionally substituted amino; and where R′ is selected from H, O,optionally substituted acyl, optionally substituted alkenyl, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedcycloalkenyl, optionally substituted cycloalkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted sulfonyl;

R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and

Q represents H, CN, halogen, trialkylsilyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted acyl, optionally substituted oxyacyl, optionallysubstituted acylamino, optionally substituted aminoacylamino, OR″, SR″or NR″R″, where each R″ independently represents, H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl and optionally substituted oxyacyl, or NR′″NR′″, whereeach R′″ independently represents H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl and optionally substituted heteroaryl.

The present invention also provides the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof:

wherein;

X represents O, S, SO, SO₂, Se, SeO, SeO₂ or NR where R is selected fromH, O, optionally substituted acyl, optionally substituted alkenyl,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, oroptionally substituted sulfonyl;

R^(1A) and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl;

R^(1C) represents C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylamino, or C₁₋₃dialkylamino;

R^(1D) represents hydroxy or amino;

L represents C═O, O, S, SO, SO₂, Se, SeO, SeO₂, C═NZ′, or NR′ where Z′is H, optionally substituted alkyl, optionally substituted aryl oroptionally substituted amino; or NR′ where R′ is selected from H, O,optionally substituted acyl, optionally substituted alkenyl, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedcycloalkenyl, optionally substituted cycloalkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted sulfonyl;

R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and

Q represents H, CN, halogen, trialkylsilyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted acyl, optionally substituted oxyacyl, optionallysubstituted acylamino, optionally substituted aminoacylamino, OR″, SR″or NR″R″, where each R″ independently represents, H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedacyl and optionally substituted oxyacyl, or NR′″NR′″, where each R′″independently represents H, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl and optionally substituted heteroaryl;

in the manufacture of a medicament for the treatment of a disease stateby inhibiting tubulin polymerisation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a graph of cell viability/proliferation relative tocontrol against concentration of CA4(1)(nM) in relation to proliferatingand quiescent endothelial cells.

FIG. 2 depicts a graph of cell viability/proliferation relative tocontrol against concentration of compound example 11 (nM) againstproliferating and quiescent endothelial cells.

FIG. 3 depicts a graph of fluorescence against time (mins) in relationto inhibition of tubulin polymerisation by CA4 (1), compound example 11,and a buffer solution.

FIG. 4 depicts a graph of % perfusion control against an amount ofcompound (mg/kg) in relation to comparative levels of vascular shutdown(reduction in tumour perfusion) between CA4P (2) and compound example 29of the present invention.

FIG. 5 depicts a graph of Tumor Volume ratio (Day*/Day 1) against time(Days) in relation to tumor growth inhibition of compound example 29 inBalb/c nu/nu mice bearing MDA-MB-231 orthotopic breast solid tumors.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

“Alkyl” refers to monovalent alkyl groups which may be straight chainedor branched and preferably have from 1 to 10 carbon atoms or morepreferably 1 to 6 carbon atoms, and even more preferably 1 to 3 carbonatoms. Examples of such alkyl groups include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.

“Alkylene” refers to divalent alkyl groups preferably having from 1 to10 carbon atoms and more preferably 1 to 6 carbon atoms, and even morepreferably 1 to 3 carbon atoms. Examples of such alkylene groups includemethylene (—CH₂—), ethylene (—CH₂CH₂—), and the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—), and the like.

“Aryl” refers to an unsaturated aromatic carbocyclic group having asingle ring (eg., phenyl) or multiple condensed rings (eg., naphthyl oranthryl), preferably having from 6 to 14 carbon atoms. Examples of arylgroups include phenyl, naphthyl and the like.

“Arylene” refers to a divalent aryl group wherein the aryl group is asdescribed above.

“Aryloxy” refers to the group aryl-O— wherein the aryl group is asdescribed above.

“Arylalkyl” refers to -alkylene-aryl groups preferably having from 1 to10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms inthe aryl moiety. Such arylalkyl groups are exemplified by benzyl,phenethyl and the like.

“Arylalkoxy” refers to the group arylalkyl-O— wherein the arylalkylgroup are as described above. Such arylalkoxy groups are exemplified bybenzyloxy and the like.

“Alkoxy” refers to the group alkyl-O— where the alkyl group is asdescribed above. Examples include, methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Alkenyl” refers to a monovalent alkenyl group which may be straightchained or branched and preferably have from 2 to 10 carbon atoms andmore preferably 2 to 6 carbon atoms and have at least 1 and preferablyfrom 1-2, carbon to carbon, double bonds. Examples include ethenyl(—CH═CH₂), n-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂),but-2-enyl (—CH₂CH═CHCH₃), and the like.

“Alkenyloxy” refers to the group alkenyl-O— wherein the alkenyl group isas described above.

“Alkenylene” refers to divalent alkenyl groups preferably having from 2to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examplesinclude ethenylene (—CH═CH—), and the propenylene isomers (e.g.,—CH₂CH═CH— and —C(CH₃)═CH—), and the like.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 10 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1, andpreferably from 1-2, carbon to carbon, triple bonds. Examples of alkynylgroups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH), pent-2-ynyl(—CH₂C≡CCH₂—CH₃), and the like.

“Alkynyloxy” refers to the group alkynyl-O— wherein the alkynyl groupsis as described above.

“Alkynylene” refers to the divalent alkynyl groups preferably havingfrom 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms.Examples include ethynylene (—C≡C—), propynylene (—CH₂—C≡C—), and thelike.

“Acyl” refers to groups H—C(O)—, alkyl-C(O)—, cycloalkyl-C(O)—,aryl-C(O)—, heteroaryl-C(O)— and heterocyclyl-C(O)—, where alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

“Oxyacyl” refers to groups HOC(O)—, alkyl-OC(O)—, cycloalkyl-OC(O)—,aryl-OC(O)—, heteroaryl-OC(O)—, and heterocyclyl-OC(O)—, where alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

“Amino” refers to the group —NR*R* where each R* is independentlyhydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl andwhere each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is asdescribed herein.

“Aminoacyl” refers to the group —C(O)NR*R* where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

“Aminoacylamino” refers to the group —NR*C(O)NR*R* where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

“Acylamino” refers to the group —NR*C(O)R* where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl are as described herein.

“Acyloxy” refers to the groups —OC(O)-alkyl, —OC(O)-aryl,—C(O)O-heteroaryl, and —C(O)O-heterocyclyl where alkyl, aryl, heteroaryland heterocyclyl are as described herein.

“Aminoacyloxy” refers to the groups —OC(O)NR*-alkyl, —OC(O)NR*-aryl,—OC(O)NR*-heteroaryl, and —OC(O)NR*-heterocyclyl where R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

“Oxyacylamino” refers to the groups —NR*C(O)O-alkyl, —NR*C(O)O-aryl,—NR*C(O)O-heteroaryl, and NR*C(O)O-heterocyclyl where R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

“Oxyacyloxy” refers to the groups —OC(O)O-alkyl, —O—C(O)O-aryl,—OC(O)O-heteroaryl, and —OC(O)O-heterocyclyl where alkyl, cycloalkyl,aryl, heteroaryl, and heterocyclyl are as described herein.

“Acylimino” refers to the groups —C(NR*)—R* where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl are as described herein.

“Acyliminoxy” refers to the groups —O—C(NR*)—R* where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl are as described herein.

“Oxyacylimino” refers to the groups —C(NR*)—OR* where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl are as described herein.

“Cycloalkyl” refers to cyclic alkyl groups having a single cyclic ringor multiple condensed rings, preferably incorporating 3 to 8 carbonatoms. Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

“Cycloalkenyl” refers to cyclic alkenyl groups having a single cyclicring and at least one point of internal unsaturation, preferablyincorporating 4 to 8 carbon atoms. Examples of suitable cycloalkenylgroups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl,cyclohex-4-enyl, cyclooct-3-enyl and the like.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Heteroaryl” refers to a monovalent aromatic heterocyclic group whichfulfils the Hückel criteria for aromaticity (ie. contains 4n+2πelectrons) and preferably has from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen, selenium, and sulfur withinthe ring (and includes oxides of sulfur, selenium and nitrogen). Suchheteroaryl groups can have a single ring (eg., pyridyl, pyrrolyl orN-oxides thereof or furyl) or multiple condensed rings (eg.,indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl orbenzothienyl).

“Heterocyclyl” refers to a monovalent saturated or unsaturated grouphaving a single ring or multiple condensed rings, preferably from 1 to 8carbon atoms and from 1 to 4 hetero atoms selected from nitrogen,sulfur, oxygen, selenium or phosphorous within the ring. The mostpreferred heteroatom is nitrogen.

Examples of heterocyclyl and heteroaryl groups include, but are notlimited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine,imidazoline, piperidine, piperazine, indoline, phthalimide,1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene,thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole,thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl,pyrrolidine, tetrahydrofuranyl, triazole, and the like.

“Heteroarylene” refers to a divalent heteroaryl group wherein theheteroaryl group is as described above.

“Heterocyclylene” refers to a divalent heterocyclyl group wherein theheterocyclyl group is as described above.

“Thio” refers to groups H—S—, alkyl-S—, cycloalkyl-S—, aryl-S—,heteroaryl-S—, and heterocyclyl-S—, where alkyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are as described herein.

“Thioacyl” refers to groups H—C(S)—, alkyl-C(S)—, cycloalkyl-C(S)—,aryl-C(S)—, heteroaryl-C(S)—, and heterocyclyl-C(S)—, where alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

“Oxythioacyl” refers to groups HO—C(S)—, alkylO—C(S)—,cycloalkylO—C(S)—, arylO—C(S)—, heteroarylO—C(S)—, andheterocyclylO—C(S)—, where alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl are as described herein.

“Oxythioacyloxy” refers to groups HO—C(S)—O—, alkylO—C(S)—O—,cycloalkylO—C(S)—O—, arylO—C(S)—O—, heteroarylO—C(S)—O—, andheterocyclylO—C(S)—O—, where alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl are as described herein.

“Phosphorylamino” refers to the groups —NR*—P(O)(R**)(OR***) where R*represents H, alkyl, cycloalkyl, alkenyl, or aryl, R** represents OR***or is hydroxy or amino and R*** is alkyl, cycloalkyl, aryl or arylalkyl,where alkyl, amino, alkenyl, aryl, cycloalkyl, and arylalkyl are asdescribed herein.

“Thioacyloxy” refers to groups H—C(S)—O—, alkyl-C(S)—O—,cycloalkyl-C(S)—O—, aryl-C(S)—O—, heteroaryl-C(S)—O—, andheterocyclyl-C(S)—O—, where alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl are as described herein.

“Sulfinyl” refers to groups H—S(O)—, alkyl-S(O)—, cycloalkyl-S(O)—,aryl-S(O)—, heteroaryl-S(O)—, and heterocyclyl-S(O)—, where alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

“Sulfonyl” refers to groups H—S(O)₂—, alkyl-S(O)₂—, cycloalkyl-S(O)₂—,aryl-S(O)₂—, heteroaryl-S(O)₂—, and heterocyclyl-S(O)₂—, where alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

“Sulfinylamino” refers to groups H—S(O)—NR*—, alkyl-S(O)—NR*—,cycloalkyl-S(O)—NR*—, aryl-S(O)—NR*—, heteroaryl-S(O)—NR*—, andheterocyclyl-S(O)—NR*—, where R* is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

“Sulfonylamino” refers to groups H—S(O)₂—NR*—, alkyl-S(O)₂—NR*—,cycloalkyl-S(O)₂—NR*—, aryl-S(O)₂—NR*—, heteroaryl-S(O)₂—NR*—, andheterocyclyl-S(O)₂—NR*—, where R* is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

“Oxysulfinylamino” refers to groups HO—S(O)—NR*—, alkylO—S(O)—NR*—,cycloalkylO—S(O)—NR*—, arylO—S(O)—NR*—, heteroarylO—S(O)—NR*—, andheterocyclylO—S(O)—NR*—, where R* is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

“Oxysulfonylamino” refers to groups HO—S(O)₂—NR*—, alkylO—S(O)₂—NR*—,cycloalkylO—S(O)₂—NR*—, arylO—S(O)₂—NR*—, heteroarylO—S(O)₂—NR*—, andheterocyclylO—S(O)₂—NR*—, where R* is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

“Aminothioacyl” refers to groups R*R*N—C(S)—, where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

“Thioacylamino” refers to groups H—C(S)—NR*—, alkyl-C(S)—NR*—,cycloalkyl-C(S)—NR*—, aryl-C(S)—NR*—, heteroaryl-C(S)—NR*—, andheterocyclyl-C(S)—NR*—, where R* is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

“Aminosulfinyl” refers to groups R*R*N—S(O)—, where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

“Aminosulfonyl” refers to groups R*R*N—S(O)₂—, where each R* isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is as described herein.

In this specification “optionally substituted” is taken to mean that agroup may or may not be further substituted or fused (so as to form acondensed polycyclic group) with one or more groups selected fromhydroxy, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy,amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, acylamino,cyano, halogen, nitro, sulfo, phosphono, phosphorylamino, phosphinyl,heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, oxyacyl,oxime, oxime ether, hydrazone, —NHC(NH)NH₂, oxyacylamino,oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl,pentafluoroethyl, trifluoromethoxy, difluoromethoxy,trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetricdi-substituted amines having different substituents selected from alkyl,aryl, heteroaryl and heterocyclyl, and the like, and may also include abond to a solid support material, (for example, substituted onto apolymer resin).

An optionally substituted amino group may also include amino acid andpeptide residues.

In some embodiments R^(1A)-R^(1B) and R^(2A)-R^(2E) are independentlyselected from the following groups:

alkyl group, preferably methyl and ethyl;

substituted alkyl group, preferably 1-hydroxyethyl, 1-thioethyl,methoxyiminomethyl, ethoxyiminomethyl, 1-(hydroxyimino)ethyl,1-(hydroxyimino)propyl, 1-hydrazinoethyl, 1-hydrazinopropyl,hydroxyiminomethyl, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl,nitromethyl, 1-nitromethyl, and 2-nitroethyl;

acyl group, preferably formyl acetyl, propionyl, benzoyl (optionallysubstituted with methyl, methoxy, halogen, nitro, trifluoromethyl orcyano);

alkoxy group, preferably methoxy and ethoxy;

oxyacyl group, preferably methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl;

acyloxy group, preferably acetoxy and propioxy;

substituted arylalkyl group, preferably 1-hydroxybenzyl, and1-thiobenzyl;

sulfinyl group, preferably methylsulfinyl, ethylsulfinyl, benzenesulfinyl (optionally substituted with methyl, methoxy, halogen, nitro,trifluoromethane or cyano), methoxysulfinyl, ethoxysulfinyl;

sulfonyl group, preferably methylsulfonyl, ethylsulfonyl,benzenesulfonyl (optionally substituted with methyl, methoxy, halogen,nitro, trifluoromethane or cyano), methoxycarbo, trifluoromethane;

oxyacylamino group, preferably methoxycarbonylamido, and ethoxycarbonylamido;

oxythioacyl group, preferably methoxythiocarbonyl andethoxythiocarbonyl;

thioacyloxy group, preferably thionoacetoxy and thionopropionoxy;

sulphinylamino group, preferably methylsulfinylamino,ethylsulfinylamino, and benzenesulfinylamino (optionally substitutedwith methyl, methoxy, halogen, nitro, trifluoromethane or cyano);

amino group;

substituted amino groups, preferably residues of L-valine, D-valine,L-alanine, D-alanine, aspartic acid, and alanylserine, N-methylamino,and N,N′-dimethylamino;

sulphonylamino group, preferably methylsulfonylamino, ethylsulfonylaminoand benzene sulfonylamino (optionally substituted with methyl, methoxy,halogen, nitro, trifluoromethane or cyano);

oxysulfinylamino group, preferably methoxysulfinylamino andethoxysulfinylamino;

oxysulfonylamino group, preferably methoxysulfonylamino andethoxysulfonylamino;

optionally substituted alkenyl group, preferably, 1-propenyl, vinyl,nitrovinyl, cyano vinyl, or trifluorovinyl and styryl (optionallysubstituted with methyl, methoxy, halogen, nitro, trifluoromethane orcyano);

alkynyl group, preferably 1-propynyl, ethynyl or trimethylsilylethynyl.

In one embodiment R^(2D), R^(2C), and R^(2B) are methoxy and L is acarbonyl group (C═O).

Accordingly, in this embodiment the compounds of the present inventionare represented by formula (Ia)

wherein;

X represents O, S, SO, SO₂, Se, SeO, SeO₂ or NR where R is selected fromH, O, optionally substituted acyl, optionally substituted alkenyl,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, andoptionally substituted sulfonyl;

R^(1A) and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl;

R^(1C) represents C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylamino, or C₁₋₃dialkylamino;

R^(1D) represents hydroxy or amino;

R^(2A) and R^(2E) independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; and

Q represents H, CN, halogen, trialkylsilyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted acyl, optionally substituted oxyacyl, optionallysubstituted acylamino, optionally substituted aminoacylamino, OR″, SR″or NR″R″, where each R″ independently represents, H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedacyl and optionally substituted oxyacyl, or NR′″NR′″, where each R′″independently represents H, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl and optionally substituted heteroaryl.

In another embodiment, R^(1A), R^(1B), R^(2A) and R^(2E) represent H andR^(1C) represents C₁₋₃ alkoxy.

Accordingly, in this embodiment the compounds of the present inventionare represented by formula (Ib)

wherein;

X represents O, S, SO, SO₂, Se, SeO, SeO₂ or NR where R is selected fromH, O, optionally substituted acyl, optionally substituted alkenyl,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, andoptionally substituted sulfonyl;

R^(1C) represents C₁₋₃ alkoxy;

R^(1D) represents hydroxy or amino;

Q represents H, CN, halogen, trialkylsilyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted acyl, optionally substituted oxyacyl, optionallysubstituted acylamino, optionally substituted aminoacylamino, OR″, SR″or NR″R″, where each R″ independently represents, H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl and optionally substitutedoxyacyl, or NR′″NR′″, where each R′″ independently represents H,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl and optionallysubstituted heteroaryl.

In a preferred embodiment R^(1C) represents methoxy.

For the compounds represented by formulae I, Ia and Ib, X is preferablyselected from O, S and NR. More preferably X is O or NR and mostpreferably X is O.

Accordingly, in another embodiment the present invention provides novelbenzofurans and pharmaceutically acceptable salts thereof of formula II:

wherein;

R^(1A) and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl;

R^(1C) represents C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylamino, or C₁₋₃dialkylamino;

R^(1D) represents hydroxy or amino;

L represents C═O, O, S, SO, SO₂, Se, SeO, SeO₂, C═NZ′, or NR′ where Z′is H, optionally substituted alkyl, optionally substituted aryl oroptionally substituted amino; and where R′ is selected from H, O,optionally substituted acyl, optionally substituted alkenyl, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedcycloalkenyl, optionally substituted cycloalkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted sulfonyl;

R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and

Q represents H, CN, halogen, trialkylsilyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted acyl, optionally substituted oxyacyl, optionallysubstituted acylamino, optionally substituted aminoacylamino, OR″, SR″or NR″R″, where each R″ independently represents, H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl and optionally substituted oxyacyl, or NR′″NR′″, whereeach R′″ independently represents H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl and optionally substituted heteroaryl.

In this embodiment it is preferred that L is a carbonyl group (C═O).Also, preferably at least one of R^(2D), R^(2C) or R^(2B) represents ahydroxy or C₁₋₃ alkoxy group. More preferably when X═O, L is a carbonylgroup an R^(2D), R^(2C) and R^(2B) represent methoxy. Even morepreferably when X═O, L is a carbonyl group, R^(2D), R^(2C), and R^(2B)represent methoxy and R^(1A), R^(1B), R^(2A), R^(2E) are H.

Furthermore, for the compounds of formula (I), (Ia), (Ib) and (II) it ispreferred that Q represents H, CN, optionally substituted C₂₋₄ alkynyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₁₋₄ alkyl,hydroxy, optionally substituted oxyacyl, NR″R″, SR″ (where each R″ isindependently H, optionally substituted C₁₋₄alkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl), NR′″NR′″(where each R′″ is independently H, C₁₋₃ alkyl), optionally substitutedacylamino, or halogen.

In some embodiments Q is independently selected from the followinggroups:

H;

CN;

halogen, preferably Br or Cl;

alkyl group, preferably methyl, ethyl, propyl, butyl;

substituted alkyl group, preferably amino, oxyacylaminoalkyl andoxysulphonylaminoalkyl;

optionally substituted alkenyl, preferably ethenyl, 2-alkylethenyl,2-oxyacylethenyl, 2-aminoacylethenyl;

optionally substituted alkynyl, preferably ethynyl, 2-alkylethynyl;

optionally substituted oxyacyl;

OR″, preferably hydroxy, methoxy, ethoxy;

NR″R″, preferably NH₂, alkylamino, dialkylamino, heteroarylamino,aminoalkylamino, hydroxyalkylamino, alkoxyalkylamino, oxyacylalkylamino,oxyacylaminoalkylamino, guanidinoalkylamino;

SR″, preferably alkylthio, aminoalkylthio, heteroarylthio,aminoalkylthio, hydroxyalkylthio, alkoxyalkylthio, oxyacylalkylthio,oxyacylaminoalkylthio, guanidinoalkylthio;

hydrazine.

The compounds of the present invention can be prepared by themulticomponent reaction system which has been described inPCT/AU02/00099 (WO 02/060872), the entire contents of which isincorporated herein by reference. In particular the compounds of thepresent invention can be prepared by the reaction sequence depicted inScheme 1 below:

Where Q is for example optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, OR″, SR″, NR″R″ orNR′″NR′″;

X is S, NR, O or Se, and

L is O, S, Se, or NR′.

As shown above in Scheme 1, the compounds of formula I in which X is NRor O can be derived from reacting together a phenol or protected amineand terminal alkyne respectively. The starting phenol or aniline andterminal alkyne can be coupled together under conditions which allow forheteroannulation to spontaneously occur so as to form the targetbenzo[b]furan or indole in a “one-pot” synthetic strategy. Thus, themetal based compound required to form (2) (when XM₁) should be such thatthe phenol or protected amine is deprotonated to form the group —OM₁ orNHM₁.

Suitable M₁ are based on Li, Na, K, Mg, Cs and Ba as well as speciesformed therefrom, for example from Grignard reagents C₁₋₄alkyl MgHal(Hal=I, Cl or Br). Suitable metal species include MgCl, MgBr or MgI.Formation of (1) can be effected by treating the corresponding phenol orprotected amine with, for example, Li₂CO₃, Na₂CO₃, K₂CO₃, MgCO₃, Cs₂CO₃,BaCO₃, MeMgCl, EtMgCl, MeMgBr, EtMgBr, MeMgI and EtMgI.

M₂ can be a hydrogen atom or metal species used in any palladium ornickel cross-coupling protocols known in the art, for example, Stille,Sonogashira, Suzuki or Negishi cross-coupling reactions using stannanes(eg, aryl or alkylstannanes, boronic acids/esters or zinc basedcompounds eg. ZnCl, ZnI₂, ZnBr₂, ZnOTf₂) for example based on Mg, Zn,Cu, B, Si, Mn, Sn, Ge or Al. Particularly suitable M₂ include ZnCl,(alkyl)₃Sn, (aryl)₃Sn, B(OR)₂ (R is, eg, H alkyl, alkenyl or alkynyl),MgBr, MgCl and MgI. Preferably the palladium catalysed couplingreactions may also include a co-catalyst, for instance, CuI, in thepresence of a suitable base such as a trialkyl amine base.

In a particularly preferred form of this aspect of the invention both M₁and M₂ are derived from a Grignard reagent such as an alkyl magnesiumhalide eg. C₁₋₄alkylMgBr, (Cl) or (I). Suitable M₁ and M₂ thus includeMgCl, MgBr and MgI.

Where X is NR, the nitrogen atom of the starting aniline is suitablyprotected by a nitrogen protecting group or as an imine Suitablenitrogen protecting groups are known to those skilled in the art oforganic synthesis and include acyl groups (eg acetyl, trifluoroacetyl),phenyl, benzyl and benzoyl. Other suitable nitrogen protecting groupsmay be found in Protective Groups in Organic Synthesis, T. W. Greene andP. Wutz, John Wiley & Son, 3^(rd) Edition.

The coupling agent used in this first step to form (2) is preferably anickel or palladium based coupling agent. Suitable coupling agents areknown in the art and include Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄,Pd(dibenzylideneacetone)₃ and PdCl₂(CH₃CN)₂.

Such coupling reactions are generally performed at temperatures belowroom temperature, most preferably at 0° C. and below. It is alsopreferred that such reactions are carried out under an inert atmosphereof either nitrogen or argon. Suitable solvents include ether solventssuch as THF and diethyl ether.

The metallated (2) can be reacted, in situ, with Halogen-R² in thepresence of a palladium catalyst in an atmosphere of CO to form (4).This may be accomplished by evacuating the inert reaction gas present inthe initial coupling step and replacing said gases with CO. In thissystem it is also preferred that the initial reaction solvent isreplaced with a more polar solvent such as, for instance, DMSO. Removalof the initial reaction solvent may be achieved in vacuo.

The preparation of benzo[b]thiophenes and benzo[b]selenophenes offormule (I), (Ia) or (Ib) are constructed using a variation of themethods described for the benzo[b]furans and indoles. In particular, thesulfur or selenium atom, X, must be protected by a suitable protectinggroup (P) to circumvent competitive coupling of a thiolate or selenoateto the aryl halide to afford xanthones or selenones. Suitable sulfur andselenium protecting groups are those which are capable of sustaining apositive charge. Examples include benzyl, allyl, and alkyl. This methodcan also be used as an alternative method for the formation ofbenzo[b]furans and indoles where X═O or NR and P=benzyl, allyl, andalkyl or where XP is an imine.

As used herein a Hal⁺ producing agent is an agent which can effectivelyact as a Hal⁺ source. Examples of Hal⁺ producing agents include I₂, Br₂,Cl₂, IBr, ICl, chloroacetamide, iodoacetamide, N-chlorosuccinamide,N-bromosuccinamide and N-iodosuccinamide. Preferably, as shown in Scheme1, the Hal⁺ producing agent is I₂. Cyclisation of (2) can be effected bytreating (2) with Hal⁺ to afford (3). Such reactions may be carried outin a variety of solvents including ionic liquids.

The coupling of (3) with the moiety M¹-aryl or R₂—C(O)—Hal to produce(4) can be carried out via palladium-mediated coupling and/ormetallation techniques as known in the art. For example, lithiation of(3) (eg using nBuLi) allows for coupling with

(Hal is I, Br or Cl, preferably Cl). In another embodiment, acarbonylation reaction can be carried out to access (4) by reacting (3)and

with a palladium catalyst in the presence of CO.

Compounds (5) can be prepared by reacting (3) with a phenolate,phenothiolate or phenoselenoate anions or with an appropriatelyactivated aniline in the presence of a base and palladium or coppercatalyst. SO, SO₂, SeO and SeO₂ derivatives can be prepared bycontrolled oxidation of the corresponding sulphides (ie, where L=S) andselenides (ie. where L=Se), respectively.

Scheme 2 represents an alternative approach to the compounds of thepresent invention.

where Q is for example H, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynl, OR″, SR″, NR″R″ orNR′″NR′″, and

X is S, NR′, O or Se.

The compounds of the present invention represented by (12) canalternatively be prepared by palladium coupling compounds (6) with analkyne (7) to form (8) under the conditions described by Bishop, B. C.,et al, Synthesis, 1997, 1315. The reaction sequence involves thedesilylation and oxidation of the C-3 silyl ether to afford a formylgroup. Desilylation can be carried out with the use of either an aqueousacid (for eg. hydrochloric acid) or by using a fluoride source.Oxidation can be carried out using CrO₃, MnO₂, dichlorodicyanoquinone(DDQ) or under Swern conditions. Addition of

to (9) can be carried out under standard 1,2-addition conditions (forexample where M₁=Li or Mg) followed by oxidation of the tertiary alcoholto ketone (10). Suitable oxidants include CrO₃, MnO₂,dichorodicyanoquinone (DDQ) or under Swern conditions. Conversion of theC-2 silyl group of (10) to a group suitable for Q addition can becarried out with ICI, IBr or Br (for when (11) bears a halogen which isI or Br) or TBAF (for when (11) is H).

If the C-2 position bears a suitable halogen, (11) can be reacted withQ-M₂ by either Suzuki coupling conditions (eg M₂=B(OH₂)), Negishicoupling conditions (eg M₂=Zn), Stille coupling conditions (egM₂=Sn(alkyl)₃), or other palladium mediated couplings where M₂=Cu, Zr,Al. These reactions provide for connection of Q to the C-2 position of(12) through a C—C bond. Connection of Q to the C-2 position of (12)through a C—N bond is also possible by direct nucleophilic substitutionof a deprotonated amine or by reaction of an amine with (11) in thepresence of a base (eg. trialkylamine, pyridine, Na₂CO₃, K₂CO₃, etc).

Scheme 3 represents a further approach to the compounds of the presentinvention.

where Q is for example H, for example optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynl, OR″, SR″,NR″R″, CN, or NR′″NR′″; and

X is S, NR′, O or Se.

Compound (10) can be prepared by palladium coupling compounds (6) withan alkyne (13) under the conditions discussed previously in relation tothe analogous reaction depicted in Scheme 2. Conversion of the C-2 silylgroup of (10) to a halogen substituent (11) can be carried out with ICI,IBr, or Br₂. Subsequent coupling of (11) with a Q group may be carriedout by reacting (11) with nucleophilic CN, NR″R″, SR″ or OR″ anions.

For both schemes 2 and 3 compounds where Q=H can be prepared byprotodesilylation of either compound (9) or (10).

An important aspect of the present invention relates to compounds whichpossess tubulin binding activity, as well as possessing selectivityand/or better solubility. In particular it has been found that theintroduction of acyclic groups into the C2-position of benzofuran,indole, benzothiophene or benzoselenophene based TPIs, can give rise toimproved anticancer properties over the same compounds which bear arylgroups at C-2. Furthermore, it has been shown that the potency of suchcompounds can be further increased by the introduction of a polarheteroatom in the C-7 position (R^(1D)) where an electron donating groupexists at C-6 (R^(1C)).

TPI compounds are important in the treatment of cancers primarily as aresult of their capacity to selectively shut down blood flow through atumour. Compounds that inhibit tumour blood flow are generally referredto as vascular disrupting agents (VDAs) (Tozer, G. M.; Kanthou, C.;

Baguley, B. C. Nature Rev., Vol. 5, 2005, 423). TPIs are VDAs becausethey inhibit a certain cell signalling pathway associated withmicrotubules, leading to interference in the regulation of thecytoskeleton of the endothelial cells that line the blood vessels of thetumour. As a result, these usually flat cells become more rounded,ultimately occluding blood flow through the vessels. The selectivityassociated with these agents results from the fact that tumourvasculature is weaker and more prone to collapse than normalvasculature. Nonetheless, a number of the dose limiting toxicitiesassociated with VDAs are due to a reduction in blood flow in healthytissues. An important aspect of the present invention is the combinationof the specific R^(1D) and R^(1C) groups together with the Q-groupconfers greater potency and selectivity upon TPI compounds (see Table1). In these preferred compounds selectivity is not simply reliant onthe predisposition of tumour vasculature towards collapse whenchallenged with a VDA but on a capacity of the VDA to distinguishbetween tumour endothelial cells and normal endothelial cells. Normalendothelial cells, found in healthy tissues, are in a “quiescent” stateand tumour endothelial cells are in an “activated” state. Most VDAs donot distinguish between these two states, for example CA4 (1) is equallypotent against quiescent and activated endothelial cells (see FIG. 1).However, it has been discovered that certain acyclic Q-groups inconjunction with specific R^(1D) and R^(1C) groups may conferselectivity upon the compounds of the formulae I, Ia, Ib and II (seeFIG. 2). These compounds (see, for instance, compound examples 9, 11 and15 in Table 1) show higher potency towards tumour endothelial cells(activated) over normal endothelial cells (quiescent).

Compound examples 11 and 29 demonstrated significantly greater potencythan CA4 (1) in inhibiting tubulin polymerisation and at shutting-downtumour vasculature (see FIGS. 3 and 4).

In another beneficial aspect the invention allows for the capacity tointroduce an acyclic Q group in compounds of formulae I, Ia, Ib and IIto affect the solubility and ADMET (absorption, distribution, metabolismexcretion and toxicity) properties of the TPI compound. Thesepharmacokinetic properties of the drug are also important in attainingthe maximum therapeutic index for a VDA. It has been reported that a lowvolume of distribution (concentration of the drug in the vasculature)and short half-life are desirable for a VDA (Rustin, J et al. J. Clin.Oncol. 2003, 21, 2815; Davies P. D. et al. Cancer Res. 2002, 62, 7247).A low volume of distribution maximises drug exposure to the targettissue, vasculature endothelium, and minimises exposure to other tissues(outside the vasculature) that may be adversely affected by TPIs. Also,tumour vasculature shuts down very quickly upon exposure to a VDA, sothat ongoing exposure systemically is undesirable as it will not furtheraffect the tumour and may lead to side-effects. A low volume ofdistribution can be achieved by increasing the hydrophilicity of acompound (introduction of polar, acidic and/or basic groups). Short-halflife can be achieved by a high rate of clearance (hepatic or renalclearance), which in turn can be achieved by incorporating readilymetabolised groups and/or in the introduction of very polar groups(polar compounds are more readily cleared through the kidneys).Compounds of formulae I, Ia, Ib and II are able to tolerate largevariations in the acyclic nature of Q whilst retaining considerablepotency (see Table 1). These compounds include systems that containpolar functionalities (carboxylates, amine and amides etc) and thatcontain metabolically labile groups (eg OH and NH groups that can beglucuronidated.

As mentioned previously, the preferred compounds of the invention havingincreased tubulin binding activity or anti-tumour vasculature activity,can be useful in methods of therapy. In particular these compounds maybe used for treating tumours. As used herein the term “tumour” is usedto define any malignant cancerous growth, and may include leukemias,melanomas, colon, lung, ovarian, skin, breast, prostate, CNS, and renalcancers, as well as other cancers.

The compounds of the invention having tubulin binding activity may alsobe used in the treatment of solid tumours, eg. breast cancer.

The invention also provides for the use of a compound of formulae (I),(Ia), (Ib), or (II) in the manufacture of a medicament for treatingtumours.

There is also provided a method of treatment of solid tumours comprisingthe administration of an effective amount of a compound of formula (I),(Ia), (Ib) or (II) to a subject in need thereof.

However, it will be understood that the compounds of the invention canbe used in the treatment of any disease state for which tubulinpolymerisation plays a crucial role.

In particular, the present compounds can be used in treatinginflammation. Such inflammatory conditions may include acute and chronicinflammatory conditions such as rheumatoid arthritis, inflammatory boweldisease, Crohn's disease, psoriasis, and the like.

Compounds of the invention which possess bioactivity, such as tubulinbinding activity, can be formulated as a composition, particularly apharmaceutical composition, together with a pharmaceutically acceptableadditive.

The compounds of the invention are administered to the subject in atreatment effective amount. As used herein, a treatment effective amountis intended to include at least partially attaining the desired effect,or delaying the onset of, or inhibiting the progression of, or haltingor reversing altogether the onset or progression of the particulardisease of condition being treated.

As used herein, the term “effective amount” relates to an amount ofcompound which, when administered according to a desired dosing regimen,provides the desired therapeutic activity. Dosing may occur at intervalsof minutes, hours, days, weeks, months or years or continuously over anyone of these periods. Suitable dosages may lie within the range of about0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. Atypical dosage is in the range of 1 μg to 1 g per kg of body weight perdosage, such as is in the range of 1 mg to 1 g per kg of body weight perdosage. In one embodiment, the dosage may be in the range of 1 mg to 500mg per kg of body weight per dosage. In another embodiment, the dosagemay be in the range of 1 mg to 250 mg per kg of body weight per dosage.In yet another embodiment, the dosage may be in the range of 1 mg to 100mg per kg of body weight per dosage, such as up to 50 mg per body weightper dosage.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the particular condition beingtreated, the severity of the condition as well as the general age,health and weight of the subject.

The active ingredient may be administered in a single dose or a seriesof doses. While it is possible for the active ingredient to beadministered alone, it is preferable to present it as a composition,preferably as a pharmaceutical composition. The formulation of suchcompositions is well known to those skilled in the art. The compositionmay contain any suitable carriers, diluents or excipients. These includeall conventional solvents, dispersion media, fillers, solid carriers,coatings, antifungal and antibacterial agents, dermal penetrationagents, surfactants, isotonic and absorption agents and the like. Itwill be understood that the compositions of the invention may alsoinclude other supplementary physiologically active agents.

The carrier must be pharmaceutically “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notinjurious to the subject. Compositions include those suitable for oral,rectal, nasal, topical (including buccal and sublingual), vaginal orparental (including subcutaneous, intramuscular, intravenous andintradermal) administration. The compositions may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then if necessary shaping the product.

Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g inert diluent, preservative disintegrant (e.g. sodium starchglycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodiumcarboxymethyl cellulose) surface-active or dispersing agent. Mouldedtablets may be made by moulding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach.

Compositions suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavoured base, usuallysucrose and acacia or tragacanth gum; pastilles comprising the activeingredient in an inert basis such as gelatine and glycerin, or sucroseand acacia gum; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Compositions suitable for topical administration to the skin maycomprise the compounds dissolved or suspended in any suitable carrier orbase and may be in the form of lotions, gel, creams, pastes, ointmentsand the like. Suitable carriers include mineral oil, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. Transdermal patches may alsobe used to administer the compounds of the invention.

Compositions for rectal administration may be presented as a suppositorywith a suitable base comprising, for example, cocoa butter, glycerin,gelatine or polyethylene glycol.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Compositions suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containanti-oxidants, buffers, bactericides and solutes which render thecomposition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets of the kind previously described.

Preferred unit dosage compositions are those containing a daily dose orunit, daily sub-dose, as herein above described, or an appropriatefraction thereof, of the active ingredient.

It should be understood that in addition to the active ingredientsparticularly mentioned above, the compositions of this invention mayinclude other agents conventional in the art having regard to the typeof composition in question, for example, those suitable for oraladministration may include such further agents as binders, sweeteners,thickeners, flavouring agents disintegrating agents, coating agents,preservatives, lubricants and/or time delay agents. Suitable sweetenersinclude sucrose, lactose, glucose, aspartame or saccharine. Suitabledisintegrating agents include cornstarch, methylcellulose,polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable flavouring agents include peppermint oil, oil of wintergreen,cherry, orange or raspberry flavouring. Suitable coating agents includepolymers or copolymers of acrylic acid and/or methacrylic acid and/ortheir esters, waxes, fatty alcohols, zein, shellac or gluten. Suitablepreservatives include sodium benzoate, vitamin E, alpha-tocopherol,ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.Suitable lubricants include magnesium stearate, stearic acid, sodiumoleate, sodium chloride or talc. Suitable time delay agents includeglyceryl monostearate or glyceryl distearate.

The novel bioactive compounds of the invention can be administered to asubject as a pharmaceutically acceptable salt thereof. It will beappreciated however that non-pharmaceutically acceptable salts also fallwithin the scope of the present invention since these may be useful asintermediates in the preparation of pharmaceutically acceptable salts.Suitable pharmaceutically acceptable salts include, but are not limitedto salts of pharmaceutically acceptable inorganic acids such ashydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic,and hydrobromic acids, or salts of pharmaceutically acceptable organicacids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic,benzoic, succinic, oxalic, phenylacetic, methanesulphonic,toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic,glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic,ascorbic and valeric acids.

Base salts include, but are not limited to, those formed withpharmaceutically acceptable cations, such as sodium, potassium, lithium,calcium, magnesium, ammonium and alkylammonium. In particular, thepresent invention includes within its scope cationic salts eg sodium orpotassium salts, or alkyl esters (eg methyl, ethyl) of the phosphategroup.

Basic nitrogen-containing groups may be quarternised with such agents aslower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl and diethylsulfate; and others.

It will be appreciated that any compound that is a prodrug of a compoundof formule (I) or (II) is also within the scope and spirit of theinvention. The term “pro-drug” is used in its broadest sense andencompasses those derivatives that are converted in vivo to thecompounds of the invention. Such derivatives would readily occur tothose skilled in the art, and include, for example, compounds where afree hydroxy group (for instance at the C-7 position or R^(1D)) isconverted into an ester, such as an acetate or phosphate ester, or wherea free amino group (for instance at the C-7 position or R^(1D)) isconverted into an amide (eg α-aminoacid amide). Procedures foresterifying, eg. acylating, the compounds of the invention are wellknown in the art and may include treatment of the compound with anappropriate carboxylic acid, anhydride or chloride in the presence of asuitable catalyst or base. A particularly preferred prodrug is adisodium phosphate ester. The disodium phosphate ester of novelcompounds of the invention may be useful in increasing the solubility ofthe compounds. This would, for instance, allow for delivery of thecompound in a benign vehicle like saline. The disodium phosphate estermay be prepared in accordance with the methodology described in Pettit,G. R., et al, Anticancer Drug Des., 1995, 10, 299.

Alternatively, the choice of an appropriate hydrophilic group as Q mayalso provide the compound with better solubility properties. This maynot only serve to avoid the need to prepare prodrugs (to increasesolubility) but may also lead to an increase in targeting tumorvasculature pharmacokinetically. Examples of solubilizing groups whichmay be present as Q include substituted amino, amino acids, tetrazoles,sulphonamides, and so on.

The compounds of the invention may be in crystalline form either as thefree compounds or as solvates (e.g. hydrates) and it is intended thatboth forms are within the scope of the present invention. Methods ofsolvation are generally known within the art.

It will also be recognised that compounds of the invention may possessasymmetric centres and are therefore capable of existing in more thanone stereoisomeric form. The invention thus also relates to compounds insubstantially pure isomeric form at one or more asymmetric centres eg.,greater than about 90% ee, such as about 95% or 97% ee or greater than99% ee, as well as mixtures, including racemic mixtures, thereof. Suchisomers may be prepared by asymmetric synthesis, for example usingchiral intermediates, or mixtures may be resolved by conventionalmethods, eg., chromatography, or use of a resolving agent.

Furthermore, depending on the substitution pattern the compounds of thepresent invention may be capable of undergoing tautomerism. Accordingly,all possible tautomers of a compound of the present invention fallwithin the scope and spirit of the invention.

The mode of proliferative diseases, such as solid tumors, ismulti-factorial. In the treatment of such diseases drugs with differentmechanisms may be combined (ie combination therapies). The compounds ofthe invention may be particularly useful in combination therapy, eg.combining the treatment with other chemotherapeutic or radiationtreatments.

For instance in order to potentiate anti-tumor treatments using thecompounds of the present invention one or more other cytotoxic compoundsincluding 5-FU, oxaliplatin, paclitaxel, gemcitabine, docetaxel,cisplatin, and doxorubicin may also be administered. The combinationtherapy may also include the addition of an angiogensis inhibitor (eg.,Avastin) or another agent or therapy (eg., radiotherapy).

Compounds that are vascularly active may be preferably administered incombination with antihypertensive (eg sublingual glyceryl trinitrite) orantihypotensive agents.

The combination partners in such therapies may be administered together,one after the other, separately in one combined unit dosage or inseparate unit dosage forms.

The synthetic methods and processes described herein to prepare thecompounds of the present invention are amenable to solid phase synthetictechniques and/or combinatorial chemistry to produce individualcompounds or libraries of compounds.

Traditionally, drug candidates have been synthesised individually, thisbeing a time consuming and laborious process if the synthetic sequencecontains even just a few steps and large numbers of compounds are to beevaluated for their biological activity. Combinatorial synthesis is anemerging technique for effecting the generation of large libraries ofmolecules and has been successfully exploited in the synthesis andevaluation of small organic libraries. These libraries and theirstarting substrates may exist as molecules in free solution orpreferably, linked to a solid support, for example, beads, pins,microtitre plates (wells) or microchips which can be polymeric, glass,silica or other suitable substrate. Chemical diversity can be achievedby either parallel or split (split and mix) syntheses wherein each stephas the potential to afford a multitude of compounds. Solution phaselibraries may be prepared via parallel syntheses wherein differentcompounds are synthesised in separate reaction vessels in parallel,often in an automated fashion. Alternatively, attachment of theindividual components employed in a synthetic sequence to an appropriatesolid phase support allows for the further creation of chemicaldiversity by utilising not only parallel synthesis but also splitsynthesis wherein the solid support containing the compounds prepared inthe prior step can be split into a number of batches, treated with theappropriate reagent and recombined.

The substrates can be attached to a solid support surface by any linkersknown in the art. The linkers may be any component capable of beingcleaved to release the substrate or final compound from the support.

Preferably, the solid support is a polymer support. Examples ofpolymeric supports currently used in solid phase synthesis include:alkenyl resins: eg. REM resins; BHA resins: eg. benzhydrylamine(polymer-bound hydrochloride, 2% crosslinked), benzhydryl chloride(polymer bound); Br-functionalised resins: eg. brominated PPOA resin,brominated Wang resin; Chloromethyl resins: eg. 4-methoxybenzhydrylchloride (polymer bound); CHO-functionalised resins: eg. indole resin,formylpolystyrene; Cl-functionalised resins: eg. Merrifield's resin,chloroacetyl (polymer bound); CO₂H-functionalised resins: eg.carboxypolystyrene; I-functionalised resins: eg. 4-iodophenol (polymerbound); Janda Jels™; MBHA resins: eg. 4-methylbenzhydrylaminehydrochloride (polymer bound), 4-hydroxymethylbenzoic acid-4-methylbenzhydrylamine (polymer bound); Amine-functionalised resins: eg.(aminomethyl)polystyrene, PAL resin, Sieber amide resin; Nitrophenylcarbonate resins: eg. 4-nitrophenyl carbonate (polymer bound);OH-functionalised resins: eg. 4-benzyloxybenzyl alcohol (polymer bound);Hydroxy methyl resins: eg. benzyl alcohol (polymer bound); HMBA resin;Oxime resins; Rink acid resin; Triazine-based resin; Trityl amineresins; Trityl resins: eg. trityl-chloride (polymer bound),2-chlorotrityl alcohol, 1,3-diaminepropane trityl.

Thus, individual compounds or libraries of compounds can be synthesisedby initially attaching the first compound substrate to a solid supportsurface which can be performed by providing a plurality of solid supportsurfaces, suitably derivatising each of the surfaces with groups capableof reacting with either the compound substrate or a linker moietyattached thereto. The various support surfaces with the attached firstcompound substrate can then be subjected to various reaction conditionsand second compound substrates to provide a library of attachedcompounds, which may, if necessary, be reacted further with third andsubsequent compound substrates or varying reactions conditions.Attachment and detachment of substrates and products can be performedunder conditions similar to those as described in Johnson, M. G., etal., Tetrahedron, 1999, 55, 11641; Han Y., et al. Tetrahedron 1999, 55,11669; and Collini, M. D., et al., Tetrahedron Lett., 1997, 58, 7963.

Those skilled in the art will appreciate that the invention describedherein in susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications which fall within thespirit and scope. The invention also includes all of the steps,features, compositions and compounds referred to or indicated in thisspecification, individually or collectively, and any and allcombinations of any two or more of said steps or features.

Certain embodiments of the invention will now be described withreference to the following examples which are intended for the purposeof illustration only and are not intended to limit the scope of thegenerality hereinbefore described.

EXAMPLES Biological Data

(i) In Vitro Studies

TABLE 1 In Vitro Data for Compounds: These are the results for growthinhibition studies of compounds using the Sulforhodamine B (SRB) orSystmex cell counting (CC) assays. IC₅₀ is the concentration required toinhibit net cell growth by 50%. Entries 1-4, 13, 36, 39, and 45 providedfor comparison, all other entries are compounds of the invention. Cancercell HUVECs^(c) Example/ line^(a): Tum: IC₅₀, nM Entry ComparatorStructure IC₅₀, nM Norm: IC₅₀, nM Comparator A

5  Tum: 1-10 Norm: 1-10 Comparator B

5  Tum: 1-10 Norm: 1-10 Comparator C Example 5

55  Tum: 10-100 Norm: 10-100 Comparator D Example 3

500   Tum: 100-1000 Norm: 100-1000 Example 6

45  Tum: 10-100 Norm: 10-100 Example 52

35  Tum: 100-1000 Norm: 100-1000 Example 53

800   Tum: >1000 Norm: >1000 Example 18

3.5 Tum: 1-10 Norm: 0.1-1 Example 9

1.2 Tum: 0.1-1 Norm: 1-10 Example 8

3.3 Tum: 1-10 Norm: 1-10 Example 10

35  Tum: 1-10 Norm: 10-100 Example 11

2.0 Tum: 0.1-1 Norm: 10-100 Comparator E Example 30

575   Tum: 100-1000 Norm: 100-1000 Example 23

260   Tum: 100-1000 Norm: 100-1000 Example 14

2.0 Tum: 0.1-1 Norm: 1-10 Example 13

8.0 Tum: 1-10 Norm: 1-10 Example 2

1-10^(b) Tum: 1-10 Norm: 1-10 Example 15

1-10^(b) Tum: 1-10 Norm: 1-10 Example 21

10-100^(b) Tum: 10-100 Norm: 10-100 Example 20

1-10^(b) Tum: 1-10 Norm: 1-10 Example 16

0.1-1^(b)   Tum: 1-10 Norm: 1-10 Example 17

1-10^(b) Tum: 1-10 Norm: 1-10 Example 19

0.1-1^(b)   Tum: 1-10 Norm: 1-10 Example 24

1-10^(b) Tum: 1-10 Norm: 1-10 Example 25

1-10^(b) Tum: 1-10 Norm: 1-10 Example 22

1-10^(b) Tum: 1-10 Norm: 1-10 Example 26

Tum: 1-10 Norm: 1-10 Example 27-HCl

Tum: 100-1000 Norm: 100-1000 Example 28

Tum: 100-1000 Norm: 10-100 Example 31

Tum: 1-10 Norm: 1-10 Example 32

Tum: 0.1-1.0 Norm: 0.1-1.0 Example 34

Tum: 1-10 Norm: 1-10 Example 35

Tum: 1-10 Norm: 1-10 Example 36

Tum: 1-10 Norm: 1-10 Example 37

Tum: 10-100 Norm: 10-100 Comparator F Example 50

Tum: 0.1-1 Norm: 0.1-1 Example 39

Tum: 0.01-0.1 Norm: 0.1-1 38. Example 40

Tum: 1-10 Norm: 10-100 Comparator G Example 51

Tum: 1-10 Norm: 1-10 Example 42

Tum: 0.1-1 Norm: 1-10 Example 43

Tum: 1-10 Norm: 1-10 Example 44

Tum: 10-100 Norm: 10-100 Example 45

Tum: 1-10 Norm: 1-10 Example 46

Tum: 10-100 Norm: 100-1000 Comparator H

Tum: 1-10 Norm: 1-10 ^(a)Unless otherwise stated the cancer cell line isMCF-7. ^(b)The cancer cell line is MDA-MB-231. ^(c)Human umbilical veinendothelial cells (HUVECs) tumour type activated endothelial cells (Tum)and normal quiescent type endothelial cells (Norm).General Description of Biological Experiments:

Tubulin Polymerisation Assay:

Tubulin polymerisation inhibition assays were performed using afluorescent-based detection kit (#BK011, Cytoskeleton) according to theinstructions of the manufacturer. The test compound was added to a 2mg/ml tubulin solution containing 20% glycerol and 1 mM GTP in 1× Buffer1 (Buffer 1: 80 mM piperazine-N,N′-bis[2-ethanesulfonic acid]sequisodium salt; 2 mM magnesium chloride; 0.5 mM Ethyleneglycol-bis(b-amino-ethyl ether)N,N,N′,N′-tetra-acetic acid, pH 6.9, 10uM fluorescent reporter). Fluorescence was measured over a period of 42minutes at 1 minute intervals. Increased fluorescence indicates increasein tubulin polymerisation. There is a ten-fold increase in the affinityof the fluorescent reporter for polymerised tubulin compared tomonomeric tubulin subunits. The result is a fluorescence signal thatclosely follows tubulin polymerisation.

Proliferation Assay—Quiescent Endothelium:

Human umbilical vein endothelial cells (CC-2519, Clonetics) were platedat 15000 cells/well in EBM2 (CC-3156, Clonetics)+0.5% FBS (CC-4101A,Clonetics)+GA-1000 (CC-4381A, Clonetics) in a 96 well plate intriplicate. Cells were cultured overnight at 37° C. 5% CO₂. Medium wassubsequently replaced with fresh medium including the compound ornegative control. Cells were cultured for a period of 48 hrs. An MTTassay was performed to measure changes in cell numbers. Briefly, 20 μlof MTT reagent was added to cells containing 100 μl of EBM2+0.5% FBS andincubated at 37° C. for 2 hours. Absorbance was measured at 492 nm.

Proliferation Assay—Activated Endothelium:

Human umbilical vein endothelial cells (CC-2519, Clonetics) were platedat 2500 cells/well in EGM2 (CC-3162, Clonetics) in a 96 well plate intriplicate. Cells were cultured overnight at 37° C. 5% CO₂. Medium wassubsequently replaced with fresh medium including the compound ornegative control. Cells were cultured for a period of 48 hrs. An MTTassay was performed to measure changes in cell numbers. Briefly, 20 μlof MTT reagent was added to cells containing 100 μl of EGM2 andincubated at 37° C. for 2 hours. Absorbance was measured at 492 nm.

(ii) In Vivo Studies

Vascular Disruption Assay:

Female athymic BALB/c-nu/nu mice (nude mice) were used for this study.Mice were between 6-8 weeks old and were purchased from the AnimalResource Centre, Perth, Western Australia and allowed to acclimatize fora couple of days. All the animals were housed under pathogen-freeconditions and cared for in accordance with Flinders University of SouthAustralia and NH&MRC guidelines and the Australian Code of Practice forthe care and use of animals for scientific purposes. The human breastcancer MDA MB 231 was grown as orthotopic xenografts in the mammary fatpad of nude mice. Each mouse was injected with 2×10⁶ cells in 50 μlDulbecco's PBS subcutaneously just above the mammary fat pad, below theright forward limb. Tumors were selected for treatment when they reacheda diameter of 100-150 mm³ (3 weeks after implantation). The testcompound (Example 29) was dissolved in saline solution and injectedintravenously at concentrations ranging from 150 mg/kg-1 mg/kg in atotal volume of 400 ul. Tumor bearing animals were injectedintravenously with 10 mg/kg Hoechst 33342, 24 hours after the injectionof the test compound. Animals were euthanised 1 minute after the Hoechst33342 injection. Tumors were recovered for histochemical analysis. Tumorperfusion analysis was performed by assessing the amount of Hoechst33342 staining across an entire tumor cross-section. 10 micron sectionsof frozen tumor biopsies were viewed under an ultraviolet light filter.Using a 4× objective lens, 8-bit monochromatic images were captured insuccession, representing the total area of the tumor section. Compositeimages of the total tumor section were generated by overlaying commonareas of the monochromatic images. Hematoxylin and Eosin-Y staining ofthe same tumor section was performed to identify non-tumor regions.Non-tumor regions were mapped on Hoechst 33342 composite images andexcluded from the quantitation analysis. Quantitation was performed bymeasuring the pixel area of Hoechst 33342 staining and the total pixelarea of the tumor region. Perfusion was expressed as a percentage ofHoechst 33342 stained area to total tumor area (see FIG. 4).

Tumor Growth Inhibition:

Balb/c nu/nu mice bearing MDA-MB-231 solid orthotopic tumors weretreated with compound Example 29 at 40 mg/kg. Animals were i.v. dosedwith a total of two cycles of Example 29 treatment. Each cycle wasdosing on days and 8 followed by a three week no-dosing period. Tumorgrowth represented as a ratio to initial tumor volume is shown over atotal of 72-days.

Tumor growth as well as animal health were monitored for up to 72 dayspost-day 1 of treatment. The results seen in this experiment (see FIG.5) clearly show tumor growth inhibition in animals treated with twocycles of Example 29. Significant differences in tumor growth betweenExample 29 treated (n=64) and vehicle treated (n=20) animals wereobserved as early as day 4 (p<0.001; unpaired t-test; Prism® analysis)through to Day 70.

Synthetic Protocols Example 1 Preparation of(6-Methoxy-7-nitrobenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone

Step 1: 2-Nitro-3-methoxyphenol

To a mixture of 2.01 g (1.3 mmol) of 2-nitroresorcinol in 15 ml of drypyridine 0.28 ml (1.36 mmol) of acetic anhydride was added dropwise at0° C. The resulting mixture was allowed to warm to room temperature.After 1 h of stirring at room temperature the solvent was removed byevaporation in vacuo and the residue diluted to 10 ml with anhydrousacetonitrile. To this 2 g of anhydrous potassium carbonate was addedfollowed by the addition of 1.5 ml of methyl iodide. The resultingsuspension was stirred overnight at room temperature, filtered off andfiltrate evaporated to dryness under reduced pressure to give 2.63 g ofcrude 3-methoxy-2-nitrophenyl acetate. This was dissolved in 15 ml ofacetonitrile and 2 ml of concentrated ammonium hydroxide was added. Theresulting mixture was allowed to stand for 30 minutes at roomtemperature and evaporated to dryness under reduced pressure. Theresidue was purified by flash column chromatography to give 1.36 g (62%yield) of pure title compound as red crystals; ¹H NMR (CDCl₃) 3.92 (s,3H, OMe); 6.51 (d, 1H, CH, J=8.5 Hz); 6.68 (d, 1H, CH, J=8.5 Hz); 7.35(m, 1H, CH); 10.18 (s, 1H, OH).

Step 2: 6-Iodo-3-methoxy-2-nitrophenol

A mixture of 1.36 g (8 mmol) of the product of Step 1 and 0.68 g (8mmol) of sodium bicarbonate was sonicated at room temperature until itbecome homogenous. The resulting mixture was cooled to 0° C. and 2.04 g(8 mmol) of iodine was added. After stirring for 1 h at room temperaturethe precipitate formed was filtered off, dried and recrystallized fromethyl ether to give 2.28 g (96% yield of pure title compound as anorange crystals; ¹H NMR (CDCl₃) 3.92 (s, 3H, OMe); 6.41 (d, 1H, CH J=9Hz); 7.82 (d, 1H, J=9 Hz); 10.37 (s, 1H, OH).

Step 3: 3-Methoxy-2-nitro-6-((trimethylsilyl)ethynyl)phenol

A modified procedure of Gottardo and Aguirre, Tetrahedron Letter,2002(43), 7091-7094 was used.

A mixture of 0.0982 g (0.33 mmol) of the product of Step 2, 8.7 mg ofcopper iodide, 13.8 mg of palladium dichlorobis(triphenyl)phosphine and0.5 ml of anhydrous triethylamine in 1.5 ml of anhydrous acetonitrilewas degassed under reduced pressure and saturated with anhydrousnitrogen at 0° C. After stirring for about 10 minutes at 0° C., 0.07 ml(0.495 mmol) of trimethylsilylacetylene was added dropwise over 10minutes. The resulting mixture was stirred overnight at room temperatureand filtered through Celite. The filtrate was evaporated under reducedpressure and the residue was purified by flash column chromatography(silica gel; methylene chloride:ethyl acetate 1:1) to give 0.05 g (57%yield of pure title product as a yellowish crystals; ¹H NMR (CDCl₃) 0.25(s, 9H, SiMe); 3.9 (s, 3H, OMe); 6.5 (d, 1H, CH, J=8.8 Hz); 7.46 (d, 1H,CH, J=8.8 Hz); 8.81 (s, 1H, OH).

Step 4:(6-Methoxy-7-nitrobenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone

A modified procedure of Hu et al, J. Org. Chem. 2002, 67, 2365-2368 wasused.

A mixture of 0.04 g (0.151 mmol) of the title compound of Step 3 and0.089 g (0.301 mmol) of 3,4,5,-trimethoxyiodobenzene, 0.1 g (0.73 mmol)of anhydrous potassium carbonate and 13.1 mg (0.01 mmol) of palladiumtetrakis(triphenylphosphine) in 5 ml of anhydrous acetonitrile wasdegassed under reduced pressure and stirred for 24 hours at 80° C. undercarbon monoxide balloon. The resulting mixture was cooled to roomtemperature, filtered through a pad of Celite and washed with 20 ml ofmethylene chloride. The combined filtrates were evaporated to drynessand the residue was purified by flash column chromatography to give0.0295 g (50% yield) of pure title compound as a colorless solid.

¹H NMR (CDCl₃) 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 4.04 (s, 3H, OMe);7.14 (s, 2H, CH aromatic); 7.15 (d, 1H, CH aromatic J=9 Hz); 8.1 (s, 1H,CH furan); 8.3 (d, 1H, J=9 Hz).

Example 2 Preparation of(7-Amino-6-methoxybenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone

A mixture of 0.022 g (0.057 mmol) of(6-methoxy-7-nitrobenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone, 0.1g of ammonium formate and 0.1 g of 10% palladium on carbon in 5 ml of amixture of 1,2-dimethoxyethane and methanol (4:1) was refluxed for 30minutes (TLC controlled reaction). After cooling to room temperature themixture was filtered through a pad of Celite and washed with methylenechloride. The filtrates were evaporated to dryness under reducedpressure and the residue was purified by flash column chromatography togive 0.011 g (55% yield) of pure title compound as a colorless solid; ¹HNMR (CDCl₃) δ 3.89 (s, 6H, OMe); 3.92 (s, 6H, OMe); 4.01 (broad s, 2H,NH₂); 6.95 (d, 1H, CH aromatic, J=8.54 Hz); 7.14 (s, 2H, CH aromatic);7.46 (d, 1H, CH aromatic, J=8.54 Hz); 8.0 (s, 1H, CH furan).

Example 3 Comparator D Preparation of2-Bromo-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran

Step 1:tert-Butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxybenzofuran(Larock coupling)

A suspension of 2-iodo-5-methoxyphenol (1.1 g, 4.41 mmol),1-(tert-butyldimethylsilyl)-3-(tert-butyldimethylsilyloxy)propyne (1.5g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate(2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100° C. wasdeoxygenated 4 times by evacuation and backfilling with nitrogen.Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vesselwas degassed twice with nitrogen. The reaction mixture was then stirredat this temperature for 4 hours (monitored by tlc) and the solvent wasremoved by distillation under vacuum. The residue was dissolved in ethylacetate (75 mL), stirred well, filtered and treated with triethylamine(5 mL). The solution was concentrated onto silica gel (10 g) andpurified by flash chromatography (silica gel, eluent=hexane/diethylether/triethylamine; 95:5:1%) to give the title compound as a yellow oil(1.09 g, 87%); ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, 1H, J=8.57 Hz), 6.97(d, 1H, J=2.15 Hz), 6.83 (dd, 1H, J=8.54, 2.18 Hz), 4.81 (s, 2H, CH₂),3.83 (s, 3H, OMe), 0.93 (s, 9H), 0.91 (s, 9H), 0.34 (s, 6H), 0.11 (s,6H).

Step 2: 2-t-Butyldimethylsilyl-3-formyl-6-methoxybenzofuran

To a solution of2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-benzofuran(1.09 g, 2.69 mmol) in methanol (100 mL) was added concentratedhydrochloric acid (200 μL) and the reaction was stirred for 30 minutes(monitored by tlc), quenched with triethylamine (2 mL) and the solventremoved by distillation under vacuum. The residue was dissolved indichloromethane (20 mL), washed with water (10 mL), dried over magnesiumsulfate, concentrated under vacuum and co-distilled with toluene (20mL); ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, 1H, J=8.57 Hz), 7.00 (d, 1H,J=2.17 Hz), 6.86 (dd, 1H, J=8.55, 2.22 Hz), 4.81 (s, 2H, CH₂), 3.84 (s,3H, OMe), 0.94 (s, 9H), 0.37 (s, 6H). The crude yellow paste (˜985 mg)was dissolved in dry dichloromethane (4 mL) and added to a stirredsolution of Collin's reagent (chromium trioxide (1.01 g), pyridine (1.65mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10minutes, filtered and the residue washed with diethyl ether (20 mL). Thefiltrate was concentrated onto silica (10 g) and purified by flashchromatography (silica gel, eluent=hexane/diethyl-ether/triethylamine(90:9:1) to afford the title compound as a light yellow oil whichcrystallized on standing (485 mg, 68%); ¹H NMR (300 MHz, CDCl₃) δ 10.25(s, 1H, CHO), 8.06 (d, 1H, J=8.61 Hz), 7.03 (d, 1H, J=2.16 Hz), 6.95(dd, 1H, J=8.60, 2.19 Hz), 3.84 (s, 3H, OMe), 0.97 (s, 9H), 0.46 (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ 186.91 (CHO), 174.18, 159.19, 159.17,132.82, 122.77, 117.34, 113.56, 95.36, 55.60, 27.04, 17.09, −5.24.

Step 3:2-t-Butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran

To a stirred solution of 3,4,5-trimethoxyiodobenzene (377 mg, 1.27 mmol)in dry tetrahydrofuran (1 mL) at −78° C. under nitrogen was addedn-butyllithium (795 μL, 1.59 mmol, 2M solution in cyclohexane) and thereaction mixture was stirred at this temperature for 40 minutes. Afterthis time a solution of2-t-butyldimethylsilyl-3-formyl-6-methoxybenzofuran (310 mg, 1.07 mmol)in dry tetrahydrofuran (1 mL) was added to the reaction dropwise viasyringe pipette. The reaction mixture was stirred at −60° C. for 20minutes and then allowed to warm to 0° C., stirred for 10 minutes,quenched with saturated ammonium chloride solution (2 mL) and dilutedwith ethyl acetate (20 mL). The organic layer was washed with water (10mL), dried over magnesium sulfate and the solvent was removed undervacuum to give a residue that was co-distilled with toluene. The crudeproduct (908 mg) was dissolved in dry tetrahydrofuran (10 mL) andtreated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59mmol) was added. The reaction mixture was stirred at room temperaturefor 16 hours (monitored by tlc) and then loaded onto silica (10 g) andpurified by flash chromatography (silica gel, eluent=hexane/diethylether/triethylamine, 90:9:1) to afford the title compound as a lightyellow paste that crystallised on standing (232 mg, 48%); ¹H NMR (300MHz, CDCl₃) δ 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H, J=2.45 Hz), 6.77(dd, 1H, J=8.76, 2.17 Hz), 6.56 (d, 1H, J=8.38 Hz), 3.94 (s, 3H, OMe),3.85 (s, 6H, 2×OMe), 3.78 (s, 3H, OMe), 1.00 (s, 9H), 0.28 (s, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 190.51 (CO), 164.77, 158.23, 158.12, 152.64,142.35, 133.19, 131.37, 123.19, 121.04, 119.63, 112.26, 107.03, 104.96,95.00, 60.47, 55.81, 55.60, 55.13, 26.43, 17.29, −6.09.

Step 4: 2-Bromo-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran

To a stirred solution of2-t-butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran(200 mg, 0.44 mmol) in 1,2-dichloroethane (2 mL) at 0° C. under nitrogenwas added bromine (23 μl, 0.44 mmol) dropwise and the reaction mixturewas stirred for 10 minutes. After this time the reaction was quenchedwith saturated sodium thiosulfate solution, extracted with ethyl acetate(20 mL), dried over magnesium sulfate and the solvent removed bydistillation under vacuum. The crude product was re-crystallised fromacetonitrile to afford the title compound as a colourless crystallinesolid (69 mg, 37%); ¹H NMR (300 MHz, CDCl₃) δ 7.45 (d, 1H, J=8.78 Hz),7.15 (s, 2H, benzoyl-Hs), 7.01 (d, 1H, J=2.18 Hz), 6.90 (dd, 1H, J=8.74,2.27 Hz), 3.94 (s, 3H, OMe), 3.85 (s, 9H, 3×OMe); ¹³C NMR (75 MHz,CDCl₃) δ 188.21 (CO), 158.29, 155.80, 152.72, 142.55, 131.99, 130.69,120.98, 119.97, 119.67, 112.90, 107.00, 95.30, 60.67, 55.94, 55.43.

Example 4 Preparation of2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran

Step 1:2-t-Butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-7-isopropoxybenzofuran(Larock coupling)

A suspension of 2-isopropoxy-3-methoxy-5-iodophenol (4.41 mmol),1-(tert-butyldimethylsilyl)-3-(tert-butyldimethylsilyloxy)propyne (1.5g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate(2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100° C. wasdeoxygenated 4 times by evacuation and backfilling with nitrogen.Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vesselwas degassed twice with nitrogen. The reaction mixture was then stirredat this temperature for 4 hours (tlc) and the solvent was removed bydistillation under vacuum. The residue was dissolved in ethyl acetate(75 mL), stirred well, filtered and treated with triethylamine (5 mL).The solution was concentrated onto silica gel (10 g) and purified byflash chromatography (silica gel, eluent=hexane/diethylether/triethylamine; 95:5:1%) to afforded the title compound as a yellowoil (1.45 g, 96%); ¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, 1H, J=8.45 Hz),6.88 (d, 1H, J=8.47 Hz), 4.80 (s, 2H, CH₂), 4.73 (m, 1H), 3.88 (s, 3H,OMe), 1.36 (d, 6H, J=6.17 Hz), 0.94 (s, 9H), 0.92 (s, 9H), 0.35 (s, 6H),0.12 (s, 6H).

Step 2: 2-t-Butyldimethylsilyl-3-formyl-6-methoxy-7-isopropoxybenzofuran

To a solution of2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-7-isopropoxybenzofuran(2.69 mmol) in methanol (100 mL) was added concentrated hydrochloricacid (200 μL) and the reaction was stirred for 30 minutes (monitored bytlc), quenched with triethylamine (2 mL) and the solvent removed bydistillation under vacuum. The residue was dissolved in dichloromethane(20 mL), washed with water (10 mL), dried over magnesium sulfate,concentrated under vacuum and co-distilled with toluene (20 mL). Thecrude product was dissolved in dry dichloromethane (4 mL) and added to astirred solution of Collin's reagent (chromium trioxide (1.01 g),pyridine (1.65 mL) in dry dichloromethane (30 mL)). The suspension wasstirred for 10 minutes, filtered and the residue washed with diethylether (20 mL). The filtrate was concentrated onto silica (10 g) andpurified by flash chromatography (silica gel,eluent=hexane/diethyl-ether/triethylamine (90:9:1) to afford the titlecompound as a light yellow oil (503 mg, 48%); ¹H NMR (300 MHz, CDCl₃) δ10.25 (s, 1H, CHO), 7.79 (d, 1H, J=8.45 Hz), 6.98 (d, 1H, J=8.46 Hz),4.65 (m, 1H), 3.89 (s, 3H, OMe), 1.35 (d, 6H, J=6.17 Hz), 0.97 (s, 9H),0.45 (s, 6H).

Step 3:2-t-Butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxybenzofuran

To a stirred solution of 3,4,5-trimethoxyiodobenzene (377 mg, 1.27 mmol)in dry tetrahydrofuran (1 mL) at −78° C. under nitrogen was addedn-butyllithium (795 μL, 1.59 mmol, 2M solution in cyclohexane) and thereaction mixture was stirred at this temperature for 40 minutes. Afterthis time a solution of2-t-butyldimethylsilyl-3-formyl-6-methoxy-7-isoproxybenzofuran (1.07mmol) in dry tetrahydrofuran (1 mL) was added to the reaction dropwisevia syringe pipette. The reaction mixture was stirred at −60° C. for 20minutes and then allowed to warm to 0° C., stirred for 10 minutes,quenched with saturated ammonium chloride solution (2 mL) and dilutedwith ethyl acetate (20 mL). The organic layer was washed with water (10mL), dried over magnesium sulfate and the solvent was removed undervacuum to give a residue that was co-distilled with toluene. The crudeproduct (908 mg) was dissolved in dry tetrahydrofuran (10 mL) andtreated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59mmol) was added. The reaction mixture was stirred at room temperaturefor 16 hours (monitored by tlc) and then loaded onto silica (10 g) andpurified by flash chromatography (silica gel, eluent=hexane/diethylether/triethylamine, 90:9:1) to afford the title compound as a lightyellow oil (498 mg, 69%); ¹H NMR (300 MHz, CDCl₃) δ 7.14 (s, 2H, benzoylHs), 6.81 (d, 1H, J=8.64 Hz), 6.77 (d, 1H, J=8.64 Hz) 4.74 (m, 1H), 3.93(s, 3H, OMe), 3.86 (s, 3H, OMe), 3.78 (s, 6H, 2×OMe), 1.39 (d, 6H,J=6.14 Hz), 1.01 (s, 9H), 0.26 (s, 6H).

Step 4:2-(tert-butyldimethylsilyloxy)-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran

To a stirred solution of2-(t-butyldimethylsilyloxy)-7-isopropoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran(160 mg, 0.31 mmol) in dry DCM (2 mL) at room temperature under nitrogenwas added solid aluminium trichloride (83 mg, 0.62 mmol) and thereaction mixture was stirred for 15 minutes (monitored by tlc). Thereaction was quenched with a saturated solution of ammonium chloride,extracted with dichloromethane and dried over magnesium sulfate. Thesolvent was removed by distillation and residue was dried by azeotropicremoval of water with toluene. The crude product was dissolved inpyridine (2 mL), acetic anhydride (1 mL) was added and reaction mixturewas stirred for 2 hours at room temperature. The solvent was distilledunder vacuum and the residue was loaded onto silica gel (1 g) andpurified by column chromatography (silica gel, eluent,hexane:diethyl-ether; 80:20) (134 mg, 84%); ¹H NMR (300 MHz, CDCl₃) δ7.14 (s, 2H, benzoyl Hs), 6.98 (d, 1H, J=8.72 Hz), 6.85 (d, 1H, J=8.72Hz), 3.93 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.80 (s, 6H, 2×OMe), 2.41 (s,3H), 0.99 (s, 9H), 0.25 (s, 6H).

Step 5:2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran

To a stirred solution of2-t-butyldimethylsilyl-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran(120 mg, 0.44 mmol) in 1,2-dichloroethane (1 mL) at room temperatureunder nitrogen was added bromine (12 μl, 0.44 mmol) dropwise and thereaction mixture was stirred at this temperature for 10 minutes. Afterthis time the reaction was quenched with saturated sodium thiosulfatesolution, extracted with ethyl acetate (20 mL), dried over magnesiumsulfate and the solvent removed by distillation under vacuum. The crudeproduct was purified by silica gel column chromatography(eluent=Hexane:diethyl ether; 8:2-7:3) to afford the title compound as acolourless crystalline solid (91 mg, 81%); ¹H NMR (300 MHz, CDCl₃) δ7.40 (d, 1H, J=8.70 Hz), 7.14 (s, 2H, benzoyl-Hs), 6.98 (d, 1H, J=8.75Hz), 3.94 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.86 (s, 6H, 2×OMe), 2.43 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ 187.95 (CO), 167.71, 152.75, 149.54,147.49, 142.59, 131.92, 131.80, 123.91, 121.84, 119.89, 117.72, 109.89,106.92, 60.69, 56.61, 56.00, 20.09.

Example 5 Comparator C Preparation of3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-benzofuran

To a stirred solution of2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-benzofuran(30 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was addedtetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution intetrahydrofuran). The reaction mixture was stirred at room temperaturefor 20 minutes (monitored by tlc), diluted with ethyl acetate (10 mL)and washed with 1M hydrochloric acid (5 mL). The organic layer was driedover magnesium sulfate and the solvent was removed under vacuum. Thecrude product was purified by flash chromatography (silica gel,eluent=hexane/diethyl ether; 7:3) to afford the title product as a creamcrystalline solid (19.3 mg, 86%); ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, 1H,J=8.97 Hz), 8.01 (s, 1H, C₂H), 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H,J=2.11 Hz), 7.00 (dd, 1H, J=8.63, 2.11 Hz), 3.93 (s, 3H, OMe), 3.90 (s,6H, 2×OMe), 3.87 (s, 3H, OMe); ¹³C NMR (75 MHz, CDCl₃) δ 188.71 (CO),158.64, 156.31, 152.82, 150.22, 141.72, 133.97, 122.58, 120.87, 118.12,113.11, 106.07, 95.53, 60.63, 55.99, 55.40.

Example 6 Preparation of3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-7-hydroxybenzofuran

Step 1: 3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-7-isopropoxybenzofuran

To a stirred solution of2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7-isopropoxy-benzofuran(0.066 mmol) in tetrahydrofuran (1 mL) was addedtetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution intetrahydrofuran). The reaction mixture was stirred at room temperaturefor 20 minutes (monitored by tlc), diluted with ethyl acetate (10 mL)and washed with 1M hydrochloric acid (5 mL). The organic layer was driedover magnesium sulfate and the solvent was removed under vacuum. Thecrude product was purified by flash chromatography (silica gel,eluent=hexane/diethyl ether; 7:3) to afford the title compound as alight yellow paste (23 mg) that was used directly in the next step; ¹HNMR (300 MHz, CDCl₃) δ 8.00 (s, 1H, C₂H), 7.78 (d, 1H, J=8.60 Hz), 7.15(s, 2H, benzoyl Hs), 7.04 (d, 1H, J=8.61 Hz), 4.73 (m, 1H), 3.93 (s, 3H,OMe), 3.92 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 1.37 (d, 6H, J=6.14 Hz).

Step 2: 3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-7-hydroxybenzofuran

A solution of3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxybenzofuran (23 mg,0.058 mmol, co-distilled with toluene before use) in dry dichloromethane(1 mL) was treated with solid aluminum chloride (16 mg, 0.116 mmol). Thereaction mixture was stirred for 20 minutes at room temperature(monitored by tlc) then quenched with saturated ammonium chloridesolution and extracted with ethyl acetate (10 mL). The organic layer waswashed with water (5 mL), dried over magnesium sulfate and concentratedunder vacuum. The crude product was purified by flash chromatography(silica gel, eluent=hexane/diethyl ether/ethyl acetate; 80:19:1) toafford the title compound as a creamy white crystalline solid (18 mg,86%); ¹H NMR (300 MHz, CDCl₃) δ 8.04 (s, 1H, C₂H), 7.63 (d, 1H, J=8.53Hz), 7.14 (s, 2H, benzoyl Hs), 7.02 (d, 1H, J=8.38 Hz), 3.97 (s, 3H,OMe), 3.93 (s, 3H, OMe), 3.89 (s, 6H, 2×OMe); ¹³C NMR (75 MHz, CDCl₃) δ188.73 (CO), 152.82, 151.24, 144.54, 143.30, 141.76, 133.97, 130.87,120.92, 120.62, 112.43, 109.16, 106.06, 60.62, 56.85, 55.97.

Example 7 Alternative synthesis of2-t-Butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzofuranStep 1: 3-(tert-Butyldimethylsilyl)-1-(3,4,5-trimethoxyphenyl)propynone

N-Butyl-lithium (1.7 M in THF, 8.12 mL, 13.8 mmol) was added dropwise toa stirred solution of t-butyl-dimethyl-silyl-acetylene (2.5 mL, 13.39mmol) in dry THF (10 mL) at −78° C. under nitrogen and the reactionmixture was stirred at between −78 to −60° C. for 1 hour. Solution of3,4,5-trimethoxy-benzaldehyde (2.7 g, 13.8 mmol) in dry THF (5 mL) wasadded to the above stirred solution dropwise and stirring was continuedfor 20 minutes. The reaction was warmed to room temperature and stirredfor one hour (monitored by tlc), quenched with saturated ammoniumchloride solution and diluted with ethylacetate (100 mL). The organiclayer was separated, dried over magnesium sulfate and the solvent wasdistilled and co-distilled with toluene to afford the crude product ascreamy paste (4.47 g). The above product was dissolved in drydichloromethane (200 mL), MnO₂ (2.5 g, 28.75 mmol) was added and thesuspension was stirred for overnight (monitored by tlc). Reaction wasfiltered through celite, washed with dichloromethane (50 mL) and solventwas distilled to afford the crude product as creamy paste (4.16 g, 93%);¹H NMR (300 MHz, CDCl₃) δ 7.41 (s, 2H, benzoyl Hs), 3.89 (s, 3H, OMe),3.87 (s, 6H, 2×OMe), 0.99 (s, 9H), 0.21 (s, 6H).

Step 2:2-t-Butyldimethylsilanyl-3(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzofuran

Procedure similar to Larock coupling described above; (3.96 g, 60%), seeabove in Example 6 for spectral data.

Example 8 Preparation of2-Ethynyl-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzofuran

To a stirred solution of2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (50mg, 0.10 mmol) in dichloromethane (1 ml) and triethylamine (0.5 ml) wasadded Pd(Ph₃P)₂Cl₂ (3.5 mg, 5 mol %) and the reaction vessel wasevacuated and backfilled with nitrogen three times.Trimethylsilylacetylene (30 mg, 0.30 mmol) and copper (I) iodide (3 mg,15 mol %) were added sequentially and the resulting dark mixture wasstirred for two hours at room temperature. After this time the reactionwas concentrated under vacuum and treated with methanol (1 ml) andpotassium hydroxide (30 mg, excess). Stirring was continued for 0.5hours then the crude mixture was concentrated onto silica andchromatographed (silica gel, gradient elution—2:1 hexanes:ethyl acetate,1:1 hexanes:ethyl acetate) to afford the product as a tan solid (10 mg,26%); ¹H NMR (CDCl₃) δ 7.26 (d, J=8.6 Hz, 1H), 7.20 (s, 2H), 6.98 (d,J=8.6 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 6H), 3.51 (s, 1H);LRMS (ESI) m/z=383 (M+H⁺).

Example 9 Preparation of7-Hydroxy-6-methoxy-2-methylsulfanyl-3-(3,4,5-trimethoxybenzoyl)benzofuran

To a suspension of2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (22mg, 0.046 mmol) in methanol (1 ml) in a screw cap vial was added sodiumthiomethoxide (16 mg, 0.23 mmol) and the resulting orange solution wasshaken for 20 minutes during which time the reaction became homogeneous.The crude reaction mixture was concentrated onto silica andchromatographed (silica gel, eluent=2:1 hexanes:ethyl acetate) to givethe product as a resin (10 mg, 54%) that could be crystallised bystanding in hexanes in the freezer overnight; ¹H NMR (CDCl₃) δ 7.08 (s,2H), 6.92 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 5.73 (br s, 1H),3.93 (s, 3H), 3.92 (s, 3H), 3.84 (s, 6H), 2.66 (s, 3H).

Example 10 Preparation of2-Hydrazino-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzofuran

To a solution of the2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (30mg, 0.062 mmol) in tetrahydrofuran (0.5 ml) was added hydrazinemonohydrate (15 μL, 0.3 mmol). A yellow precipitate immediately formedand the heterogeneous mixture was heated to 60° C. for 1 hour duringwhich time more solid separated from the reaction. After cooling, thesolid product was collected by filtration, washed with ether and driedunder vacuum (6 mg, 25%); ¹H NMR (d⁶-DMSO) δ 9.70 (br s, 1H), 9.27 (brs, 1H), 6.85 (s, 2H), 6.68 (d, J=8.5 Hz, 1H), 6.21 (d, J=8.5 Hz, 1H),5.00 (br s, 2H), 3.73 (s, 6H), 3.71 (s, 3H), 3.70 (s, 3H).

LRMS (ESI) m/z=389 (M+H⁺), 372 (M+H⁺-NH₃).

Example 11 Preparation of2-Methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran

To a stirred solution of2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (20mg, 0.042 mmol), methyl-boronic acid (40 mg, 0.67 mmol), in 1,4-dioxane(2 mL) at 90° C. was added tetrakis-triphenylphosphine palladium (11 mg,0.01 mmol) followed by the addition of a solution of sodium bicarbonate(40 mg, 0.48 mmol) in distilled water (0.5 mL). The reaction mixtureturned red after 5 minutes. After 2 hours (tlc) the reaction mixture wasbrought to room temperature and was added saturated ammonium chloride (2mL) and diluted with dichloromethane (20 mL). The organic layer wasseparated and washed with water, dried over magnesium sulfate and thesolvent was removed by distillation under vacuum. The residue waspurified by PTLC (eluent=Dichloromethane/Methanol, 1:1) to give thetitle compound (actate cleaved during reaction) as a fluffy white solid;(3 mg, 19%).

Example 12 Alternative Method for preparing2-Methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran(Negishi Coupling)

To a stirred solution of zinc-bromide (592 mg, 2.63 mmol) in dry THF(1.5 mL) at 0° C. was added the solution of methyl lithium (1.6 Msolution in diethyl-ether, 2.6 mL, 4.15 mmol) and the reaction mixturewas stirred for 2 hours. Solid2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (300mg, 0.63 mmol) (compound of example 4) was added and the ether wasremoved under vacuum and to the rest suspension was addeddichlorobis(triphenylphosphine)palladium catalyst (21 mg) and catalyticamount of copper (I) iodide. The reaction mixture was stirred at roomtemperature for 36 hours (monitored by tlc), quenched with saturatedammonium chloride solution and extracted with dichloromethane (10 mL),dried over magnesium sulfate and solvent distilled under vacuum and theproduct was purified by silica gel column (eluent=hexane/ethyl acetate;8:2). The product was crystallized in methanol (106 mg, 46%); ¹H NMR(300 MHz, CDCl₃) δ 7.09 (s, 2H, benzoyl Hs), 6.93 (d, 1H, J=8.54 Hz),6.83 (d, 1H, J=8.56 Hz), 5.70 (bs, 1H, OH), 3.93 (s, 3H, OMe), 3.92 (s,3H, OMe), 3.83 (s, 6H, 2×OMe), 2.54 (s, 3H, 2-Me)

Example 13 Preparation of[7-Hydroxy-6-methoxy-2-{(E)-pent-1-enyl)benzofuran-3-yl]-3,4,5-trimethoxy-phenyl)methanone

As for the Suzuki reaction above (see Example 11), except themethylboronic acid was replaced withtrans-4,4,5,5-tetramethyl-2-pent-1-enyl-1,3,2-dioxaborolane theidentical procedure afforded the title compound as light creamy solid(24 mg, 27%); ¹H NMR (300 MHz, CDCl₃) δ 7.12 (s, 2H, benzoyl Hs), 6.97(d, 1H, J=8.55 Hz), 6.83 (d, 1H, J=8.61 Hz), 6.87-6.78 (m, 1H), 6.45(and 1H, J=14.44 Hz), 5.68 (b, 1H, OH), 3.93 (s, 6H, 2×OMe), 3.83 (s,6H, 2×OMe), 2.2-2.15 (m, 2H), 1.50-1.41 (m, 2H), 0.92 (t, 3H, J=7.41Hz).

Example 14 Preparation of(E)-3-[7-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-yl]-acrylicacid methyl ester

Mixture of2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50mg, 0.10 mmol) and methylacrylate (0.5 mL, excess) in a mixture ofacetonitrile: TEA; 1 mL:0.5 mL was degassed with nitrogen and palladiumacetate (10 mg) was added to it. Reaction mixture was stirred for onehour under nitrogen at reflux, more palladium acetate (15 mg) was addedand the refluxing was continued for 7 hours (monitored by tlc). Methanol(1 mL) was added followed by the addition of potassium carbonate (70 mg,0.51 mmol) and stirring was continued for 1 hour. Solvent was distilledand the crude material was purified over silica gel column (eluentHexane:diethylether; 1:1) to afford the title compound as yellowcrystalline solid (17 mg, 37%); ¹H NMR (300 MHz, CDCl₃) δ 7.61 (d, 1H,J=15.76 Hz), 7.14 (s, 2H, benzoyl Hs), 6.98 (d, 1H, J=8.64 Hz), 6.89 (d,1H, J=8.69 Hz), 6.81 (d, 1H, J=15.78 Hz), 3.96 (s, 3H, OMe), 3.95 (s,3H, OMe), 3.81 (s, 6H, 2×OMe), 3.77 (bs, 3H, OMe).

Example 15 Preparation of(E)-3-[7-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)benzofuran-2-yl]-acrylamide

As for Example 14 above except methyl acrylate was substituted withacrylamide, gave the title compound as light yellow solid (5 mg, 17%);¹H NMR (300 MHz, CD₃OD) δ: 7.48 (d, 1H, J=15.5 Hz), 7.18 (s, 2H, benzoylHs), 7.00 (d, 1H, J=8.65 Hz), 6.94 (d, 1H, J=15.52 Hz), 6.88 (d, 1H,J=8.62 Hz), 4.55 (b, 2H, NH₂), 3.91 (s, 3H, OMe), 3.87 (s, 3H, OMe),3.79 (s, 6H, 2×OMe).

Example 16 Preparation of2-cyano-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran

A mixture of2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (25mg, 0.05 mmol) and sodium cyanide (15 mg, 0.38 mmol) in dry DMSO (1 mL)under nitrogen at room temperature was stirred for 3.5 hours (monitoredby tlc), quenched with saturated ammonium chloride solution and dilutedwith ethylacetate (20 mL). The organic layer was separated, dried overmagnesium sulfate and the solvent distilled to afford the crude materialwhich was purified over silica gel column (eluent—Hexane:diethyl-ether1:1 to 0:100) to afford the desired product as pale cream solid (13 mg,65%); ¹H NMR (300 MHz, CDCl₃) δ: 7.29 (d, 1H, J=8.71 Hz), 7.19 (s, 2H,benzoyl Hs), 6.06 (d, 1H, J=8.77 Hz), 5.82 (b, 1H, OH), 3.99 (s, 3H,OMe), 3.96 (s, 3H, OMe), 3.88 (s, 6H, 2×OMe).

Example 17 Preparation of7-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-methylcarboxylate

To a solution of2-cyano-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (20mg, 0.05 mmol) in a mixture of methanol:acetonitrile; 2 mL:1 mL wasadded potassium carbonate (50 mg, 0.36 mmol) and the reaction mixturewas stirred for 16 hours at room temperature (monitored by tlc). Solventwas distilled and to the residue was added saturated ammonium chloridesolution (2 mL) and ethyl acetate (15 mL) and the crude mixture wasstirred for 15 minutes. The organic layer was separated and dried overmagnesium sulfate. The crude material was purified over silica gelcolumn (eluent—neat diethyl-ether to diethyl-ether: ethyl-acetate 80:20)to afford the title compound as pale cream solid (9 mg, 42%); ¹H NMR(300 MHz, CDCl₃) δ: 7.12 (s, 2H, benzoyl Hs), 6.99 (d, 1H, J=8.57 Hz),6.93 (d, 1H, J=8.72 Hz), 5.28 (b, 1H, OH), 3.96 (s, 3H, OMe), 3.93 (s,3H, OMe), 3.81 (s, 6H, 2×OMe), 3.68 (bs, 3H, OMe).

Example 18 Preparation of2-(N-Methylamino)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran

To a stirred solution of2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (20mg, 0.066 mmol) in acetonitrile (3 mL) was added the solution ofmethyamine (1 mL, excess as reactant and base), and the reaction mixturewas stirred at room temperature for 1 hour when the precipitatesappeared. The solvent was distilled under vacuo and the crude wasdissolved in tetrahydrofuran (2 mL), 1M hydrochloric acid (1 mL) wasadded and the reaction mixture was stirred for 1 hour then diluted withdichloromethane (10 mL) and washed with water. The organic layer wasdried over magnesium sulfate and solvent was distilled under vacuo. Thecrude was purified by PTLC (eluent=Hexane:ethylacetate:triethylamine;2:8:1%) to gave the title compound as a yellow-green solid (5 mg, 29%);¹H NMR (300 MHz, CDCl₃) δ 8.91 (broad, 1H, NH), 6.93 (s, 2H, benzoylHs), 6.59 (d, 1H, J=8.56 Hz), 6.46 (d, 1H, J=8.51 Hz), 5.61 (bs, 1H,OH), 3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.28 (d,3H, J=5.28 Hz).

Example 19 Preparation of(2-Amino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5-trimethoxyphenyl)-methanone

Step 1:(2-Benzylamino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (140mg, 0.29 mmol) was dissolved in dry pyridine (2 mL) and benzylamine (500μL, excess) was added to it and the reaction mixture was stirred at 80°C. for 1 hour. Solvent was distilled and the crude product was purifiedover silica gel column to afford the title compound as light yellowsolid (112 mg, 83%); ¹H NMR (300 MHz, CDCl₃) δ: 9.27 (b, 1H, NH),7.39-7.32 (m, 5Hs, Ar Hs), 6.96 (s, 2H, benzoyl Hs), 6.61 (d, 1H, J=8.47Hz), 6.50 (d, 1H, J=8.10 Hz), 4.83 (d, 2H, J=4.95 Hz, Benzyl Hs), 3.91(s, 3H, OMe), 3.85 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe).

Step 2:(2-Amino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5-trimethoxy-phenyl)methanone

A mixtuer of2-benzylamino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(105 mg, 0.23 mmol) and Pd/C (10%, 100 mg) in a mixture of solventsethylacetate/THF/water/HCl (3 mL:2 mL:1 mL) 2 drops was stirred at roomtemperature for 2.5 hours under the atmosphere of hydrogen (monitored bytlc). The mixture was filtered through celite, washed withdichloromethane (5 mL×3) and solvent was distilled to afford the productas green yellow solid which was purified by flash column to gave thecrystalline yellow green solid (79 mg, 93%); ¹H NMR (300 MHz, CDCl₃) δ:6.98 (s, 2H, benzoyl Hs), 6.93 (bs, 2H, NH2), 6.63 (d, 1H, J=8.18 Hz),6.52 (d, 1H, J=8.41 Hz), 5.65 (bs, 1H, OH), 3.92 (s, 3H, OMe), 3.86 (s,3H, OMe), 3.84 (s, 6H, 2×OMe).

Example 20 Preparation of[7-Hydroxy-2-(2-hydroxy-ethylamino)-6-methoxy-benzofuran-3-yl]-(3,4,5-trimethoxy-phenyl)methanone

When benzylamine was substituted with ethanolamine as in Example 19 (seestep 1) the same procedure gave the title compound as greenish yellowsolid (29 mg, 67%); ¹H NMR (300 MHz, CDCl₃) δ: 9.13 (b, 1H, NH), 6.94(s, 2H, benzoyl Hs), 6.60 (d, 1H, J=8.54 Hz), 6.47 (d, 1H, J=8.55 Hz),3.94-3.89 (m, 4H), 3.91 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.83 (s, 6H,2×OMe).

Example 21 Preparation of[2-(2-Dimethylamino-ethylamino)-7-hydroxy-6-methoxy-benzofuran-3-yl-(3,4,5-trimethoxy-phenyl)methanone

When benzylamine was substituted with N,N′-dimethylethylenediamine as inExample 20 (see step 1) the same procedure gave the title compound asgreenish yellow solid (25 mg, 54%); ¹H NMR (300 MHz, CDCl₃) δ 9.1 (b,1H, NH), 6.95 (s, 2H, benzoyl Hs), 6.60 (d, 1H, J=8.44 Hz), 6.48 (d, 1H,J=8.48 Hz), 3.90 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.83 (s, 6H, 2×OMe),3.82-3.83 (m, 2H), 2.65 (t, 2H, J=5.63 Hz), 2.34 (s, 6H).

Example 22 Preparation of(2-N,N′-Dimethylamino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

The 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran(40 mg, 0.084 mmol) was dissolved in THF (1 mL) and solution ofN,N′-dimethyl-amine (2M solution in THF, 0.5 mL) was added to it. Thereaction mixture was stirred for overnight. Solvent was distilled andthe crude was purified over silica gel plate to afford the titlecompound as yellow solid (18 mg, 54%); ¹H NMR (300 MHz, CDCl₃) δ 7.11(s, 2H, benzoyl Hs), 6.61 (d, 1H, J=8.55 Hz), 6.44 (d, 1H, J=8.51 Hz),3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe).

Example 23 Preparation of[7-hydroxy-6-methoxy-3(3,4,5-trimethoxy-benzoyl)-benzofuran-2-ylamino]-aceticacid

A mixture of2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50mg, 0.10 mmol), glycine (18 mg, 0.29 mmol) and potassium carbonate (29mg, 0.21 mmol) in a mixture of MeCN/water 80:20 (5 mL) was refluxed forsix hours. Solvent was distilled and the residue was taken inwater:dichloromethane 1:2 (30 mL) and stirred for 20 minutes. Aqueouslayer was separated, washed with dichloromethane (20 mL) and acidifiedwith 2 drops of concentrated HCl and was diluted with dichloromethane(50 mL) and was stirred for 30 minutes. The organic layer was separatedand dried over magnesium sulfate and solvent was distilled to afford thetitle compound as yellow powder (23 mg, 51%); ¹H NMR (300 MHz, Acetoned₆) δ 9.09 (b, 1H, NH), 6.97 (s, 2H, benzoyl Hs), 6.74 (d, 1H, J=8.53Hz), 6.45 (d, 1H, J=8.48 Hz), 4.48 (d, 2H, J=4.28 Hz), 3.82 (s, 6H,2×OMe), 3.79 (s, 3H, OMe), 3.78 (s, 3H, OMe).

Example 24 Preparation of[7-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-ylamino]-aceticacid methyl ester

[7-hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-ylamino]aceticacid (30 mg, 0.07 mmol) was dissolved in dry methanol (5 mL) andtrimethylsilyl chloride (100 μL) was added to it. The reaction wasstirred at room temperature for 6 hours (monitored by tlc). Solvent wasdistilled under vacuum and the crude was purified over silica gel plateto afford the title compound as yellow solid (23 mg, 79%); ¹H NMR (300MHz, CDCl₃) δ 9.11 (b, 1H, NH), 6.97 (s, 2H, benzoyl Hs), 6.62 (d, 1H,J=8.56 Hz), 6.51 (d, 1H, J=8.49 Hz), 4.42 (d, 1H, J=6.09 Hz), 3.91 (s,3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.81 (s, 3H, OMe).

Example 25 Preparation of[7-Hydroxy-6-methoxy-2-(pyridin-3-ylamino)-benzofuran-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

A mixture of2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50mg, 0.10 mmol) and 3-amino-pyridine (30 mg, 0.30 mmol) in a mixture ofsolvent acetonitrile:water (8:2, 5 mL) was refluxed with stirring for 6hours. The solvent was distilled under vacuum and the residue waspurified over silica gel column to afford the title compound as yellowsolid (11 mg, 23%); ¹H NMR (300 MHz, CDCl₃) δ 11.22 (s, 1H), 8.77 (b,1H), 8.42 (b, 1H), 8.01 (bd, 1H), 7.28 (b, 1H), 7.03 (s, 2H, benzoylHs), 6.71 (d, 1H, J=8.82 Hz), 6.63 (d, 1H, J=8.37 Hz), 3.94 (s, 3H,OMe), 3.90 (s, 3H, OMe), 3.86 (s, 6H, 2×OMe).

Example 26 Preparation oftert-Butyl-2-(7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzofuran-2-ylamino)ethylcarbamate

A mixture of 0.05 g (0.1 mmol) of2-bromo-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzofuran-7-yl acetateand 0.057 g (0.35 mmol) of tert-butyl 2-aminoethylcarbamate (Fontand &Pignatti J. Label. Compd. Radiopharm., 2002, 45, 899-909) in 0.5 ml ofanhydrous pyridine was stirred overnight at room temperature undernitrogen atmosphere. After evaporation of solvent in vacuo, the residuewas diluted to 10 ml with ethyl acetate and washed with saturatedammonium chloride, water and dried over anhydrous magnesium sulfate.Filtration and evaporation of solvent gave 0.054 g of residue, which waspurified by flash column chromatography to give the title compound as acreamy solid (0.031 g, 59%); ¹H NMR (CDCl₃) δ 1.42 (s, 9H, Me BOC); 3.45(m, 2H, CH₂); 3.75 (m, 2H, CH₂); 3.84 (s, 6H, OMe); 3.86 (s, 3H, OMe);3.91 (s, 3H, OMe); 4.86 (broad s, 1H, NH); 5.76 (broad s, 1H, OH); 6.47(d, 1H, CH aromatic, J=8.52 Hz); 6.6 (d, 1H, CH aromatic, J=8.52 Hz);6.94 (s, 2H, CH aromatic); 9.04 (m, 1H, NH).

Example 27 Preparation of[2-(2-aminoethylamino)-7-hydroxy-6-methoxybenzofuran-3-yl](3,4,5-trimethoxyphenyl)methanoneTrifluoroacetate Salt

0.026 g (0.05 mmol) of[2-(2-aminoethylamino)-7-hydroxy-6-methoxybenzofuran-3-yl](3,4,5-trimethoxyphenyl)methanonewas dissolved in 1 ml of anhydrous trifluoroacetic acid. After stirringfor 1 h at room temperature the solvent was removed under reducedpressure and the residue was suspended in 2 ml of anhydrous methylenechloride and evaporated under reduced pressure. The residue was washedwith 2 ml of anhydrous methylene chloride to give the title compound asa yellowish solid (0.011 g, 42%); ¹H NMR (CD₃OD) δ 3.31 (tr, 2H, CH₂,J=%0.84 Hz); 3.8 (s, 9H, OMe); 3.83 (s, 3H, OMe); 3.92 (tr, 2H, CH,J=5.84 Hz); 6.33 (d, 1H CH aromatic, J=8.52 Hz); 6.69 (d, 1H, CHaromatic, J=8.52 Hz); 6.95 (s, 2H, CH aromatic).

Example 28 Preparation of1-[2-(7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzofuran-2-ylamino)ethyl]guanidine

To a mixture of 0.02 g (0.046 mmol) of2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran and0.02 g (0.11 mmol) of N-(2-aminoethyl)guanidine dihydrochloride(prepared by Fontand & Pignatti, J. Label. Compd. Radiopharm., 2002, 45,899-909) in 0.5 ml of anhydrous dimethylacetamide 0.032 ml (0.184 mmol)of N,N-diisopropylethylamine was added at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 30 h at roomtemperature, then evaporated to dryness in vacuo. The residue waspurified by flash column chromatography (silica gel, acetonitrile/water9:1) to give the title compound as a yellowish solid (0.006 g, 28%); ¹HNMR (CD₃OD) δ 3.55 (tr, 2H, CH₂, J=6 Hz); 3.7-3.86 (m, 14H, OMe×4, CH₂);4.82 (s, H₂O); 6.32 (d, 1H, CH aromatic, J=8.47 Hz); 6.69 (d, 1H, CHaromatic, J=8.47 Hz); 6.94 (s, 2H, CH aromatic). MS (m/z) 458.9; 459.9,460.9.

Example 29 Preparation of Disodium6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-yl phosphate

Step 1: Dibenzyl6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-yl phosphate

To a mixture of 0.081 g (0.22 mmol) of(7-hydroxy-6-methoxy-2-methylbenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone,0.086 g (0.261 mmol) of carbon tetrabromide and 0.063 ml (0.283 mmol) ofdibenzylphosphite in 2.5 ml of anhydrous acetonitrile 0.046 ml ofanhydrous triethylamine was added dropwise at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 2 h at roomtemperature, then diluted to 20 ml with ethyl acetate, washed with waterbrine, dried over anhydrous magnesium sulfate, filtered off andevaporated to dryness under reduced pressure. The residue was purifiedby flash column chromatography (dichloromethane/ethyl acetate, 9:1) togive the title compound as a colorless foam (0.13 g, 94%); ¹H NMR(CDCl₃) δ 2.42 (s, 3H, Me-2); 3.83 (s, 1H, OMe); 3.93 (s, 3H, OMe); 5.33(m, 4H, CH₂Ph); 6.89 (d, CH aromatic, J=8.7 Hz); 7.21 (dd, 1H, CHaromatic, J=8.72 Hz; J=1.2 Hz); 7.08 (s, 2H, CH aromatic); 7.29-7.43 (m,10H, CH aromatic).

Step 2: Disodium6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-yl phosphate

To a stirred solution of 0.122 g (0.193 mmol) of the product from Step 1in 1 ml of anhydrous acetonitrile 0.075 ml (0.58 mmol) ofbromotrimethylsilane was added at −5° C. under nitrogen atmosphere. Theresulting mixture was stirred for 1 h at 0° C., then evaporated todryness in vacuo. The residue was diluted to 5 ml with anhydrousmethanol and pH of the solution was brought up about 10 by the additionof sodium methoxide. After evaporation of the resulting mixture underreduced pressure the solid residue was washed with anhydrous isopropanol(4×1.5 ml) and anhydrous ethanol (3×1.5 ml) and dried under vacuum togive 0.062 g (65% yield) of title compound as an colorless solid; ¹H NMR(D₂O) δ 2.37 (s, 3H, Me-2); 3.76 (s, 6H, OMe); 3.79 (s, 3H, OMe); 3.82(s, 3H, OMe); 4.66 (s, H₂O); 6.93 (d, 1H, CH aromatic, J=8.6 Hz); 7.04(d, 1H, CH aromatic, J=8.6 Hz); 7.10 (s, 2H, CH aromatic).

Example 30 Preparation of(2-Hydroxy-6-methoxybenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone

Step 1: 3-Oxo-3-(3,4,5-trimethoxyphenyl)propionic acid

10 ml of 2M solution of n-butyllithium in cyclohexane was added dropwiseover 10 minutes to a stirred solution of 5.08 g (20 mmol) ofbis(trimethylsilyl)malonate in 40 ml of anhydrous ether under nitrogenatmosphere at −60° C. The mixture was then allowed to warm to 0° C. andthe solution of 2.3 g (10 mmol) of 3,4,5-trimethoxybenzoyl chloride in20 ml of anhydrous ethyl ether was added in one portion. The resultingmixture was stirred for 10 min. at 0° C. then shaken with 100 ml of 5%aqueous sodium bicarbonate for 5 minutes. The aqueous phase wasacidified to pH=˜1 with cold 4N sulfuric acid and extracted with ethylether (3×100 ml). The combined extracts were dried over anhydrousmagnesium sulfate, filtered off and evaporated to dryness to give thetitle compound as a creamy crystals (1.82 g, 71.6%); ¹H NMR (CDCl₃) δ3.8-3.92 (m, 9H, OMe); 4.03 (s, 1.8H, CH₂); 5.62 (s, 0.2H, CH enol); 7.2(s, 2H, CH aromatic).

Step 2: 3-Methoxyphenyl 3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate

To a mixture of 0.27 g (1.06 mmol) of the product of Step 1 and 0.13 g(1.06 mmol) of 3-methoxyphenol in 2 ml of anhydrous methylenechloride0.16 ml (1.06 mmol) of diisopropylcarbondiimide was added at roomtemperature. The resulting mixture was stirred for 24 hours at roomtemperature and filtered off. The filtrate was evaporated to dryness andpurified by flash column chromaytography (silica gel; methylenechloride) to give the title compound as a colorless crystals (0.185 g,49%); ¹H NMR (CDCl₃) δ 3.77 (s, 3H, OMe); 3.91 (s, 6H, OMe); 4.17 (s,3H, OMe); 4.173 (s, 2H, CH₂); 6.6-6.8 (m, 3H, CH aromatic); 7.2-7.3 (m,3H, CH aromatic).

Step 3:(2-Hydroxy-6-methoxybenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone

The procedure of Baumm et al, Synthetic Communication 1987, 17(14),1709-1716, was used. To a stirred solution of 0.0561 g (0.156 mmol) ofthe product of Step 2 and 0.041 g (0.171 mmol) of4-acetamidobenzenesulfonyl azide in 2 ml of anhydrous acetonitrile 0.065ml (0.47 mmol) of triethylamine was added at 0° C. After stirring for 3hours at room temperature the solvent was evaporated to dryness underreduced pressure and the residue was purified by flash columnchromatography (silica gel, methylene chloride) to give 0.059 g (98%yield) of 3-methoxyphenyl2-diazo-3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate. This was dissolvedin 2 ml of anhydrous methylene chloride and 3.5 mg (7.9 μmol) of rhodium(III) acetate was added at room temperature under nitrogen atmosphere.The resulting mixture turned deep green after 1 h of stirring at roomtemperature. After filtration through Celite and washing with freshmethylene chloride, the filtrate was evaporated to dryness under reducedpressure to give the title compound as an deep yellow crystals (0.049 g,91%); ¹H NMR (CDCl₃) δ 3.8 (s, 3H, OMe); 3.9 (s, 6H, OMe); 3.94 (s, 3H,OMe); 6.58 (dd, 1H, CH aromatic, J=2.4 Hz; 8.6 Hz); 6.76 (d, 1H CHaromatic; J=2.4 Hz); 7.04 (s, 2H, CH aromatic); 7.25 (d, 1H, CHaromatic, J=8.6 Hz).

Example 31 Preparation of2-Butyl-3-(3,4,5-trimethoxyphenyl)-7-hydroxy-6-methoxy-benzo[b]furan

This compound was prepared according to the procedure described forExample 12, except that butyllithium was used in place of methyllithium.

¹H NMR (300 MHz, CDCl₃) δ-7.10 (s, 2H, benzoyl Hs), 6.87 (d, J=8.61 Hz,1H), 6.82 (d, J=8.58 Hz, 1H), 5.71 (s, 1H, OH), 3.94 (s, 3H, OMe), 3.93(s, 3H, OMe), 3.82 (s, 6H, 2×OMe), 2.87 (t, 2H, J=7.54 Hz), 1.81-1.71(m, 2H), 1.38-1.70 (m, 2H), 0.87 (t, 3H, J=7.37 Hz).

Example 32 Preparation of2-Ethyl-3-(3,4,5-trimethoxyphenyl)-7-hydroxy-6-methoxy-benzo[b]furan

This compound was prepared according to the procedure described forExample 12, except that ethyllithium was used in place of methyllithium.

¹H NMR (300 MHz, CDCl₃) δ-7.11 (s, 2H, benzoyl Hs), 6.91 (d, J=8.61 Hz,1H), 6.83 (d, J=8.58 Hz, 1H), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.82(s, 6H, 2×OMe), 2.88 (q, 2H, J=15.00, 7.52 Hz), 1.33 (t, 3H, J=7.49 Hz).

Example 33 Preparation of2-Bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-acetoxy-benzo[b]furan

To a stirred solution of2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan(Example 11) (985 mg, 2.65 mmol) in dry pyridine (10 mL) under nitrogenwas added acetic anhydride (540 μL, 5.71 mmol) and after 0.5 hours moreof acetic anhydride (540 μL, 5.71 mmol) was added and the solution wasstirred for 1.5 hours. The solvent was distilled and the residue wastaken in dichloromethane (20 mL), washed with 1M HCl. The organic layerwas separated and dried over magnesium sulphate and solvent wasdistilled to gave the crude product which was purified over silica gelcolumn to afford the title compound as a creamy solid (1.09 gm, 99%). ¹HNMR (300 MHz, CDCl₃) δ 7.28 (d, J=8.74 Hz, 1H), 7.09 (s, 2H, benzoylHs), 6.90 (d, J=8.69 Hz, 1H), 3.93 (s, 3H, OMe), 3.87 (s, 6H, 2×OMe),3.84 (s, 3H, OMe), 2.51 (s, 3H), 2.43 (s, 3H). The2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-O-acyl-benzo[b]furan(390 mg, 0.94 mmol, as obtained above) was dissolved in dry carbontetrachloride (10 mL) and catalytic amount of benzoyl peroxide was addedto it followed by the addition of N-bromosuccinamide (167 mg, 0.94mmol). The mixture was stirred at reflux for 3 hours and the solvent wasdistilled under vacuum. The residue was dissolved in DCM (20 mL) and waswashed with 10% sodium bicarbonate solution and water. The organic layerwas separated, dried over magnesium sulphate and the solvent wasdistilled under vacuum to gave the title compound as creamy white solid(461 mg, 99%). ¹H NMR (300 MHz, CDCl₃) δ 7.28 (d, J=8.76 Hz, 1H), 7.14(s, 2H, benzoyl Hs), 6.95 (d, J=8.75 Hz, 1H), 4.6 (s, 2H), 3.94 (s, 3H,OMe), 3.89 (s, 3H, OMe), 3.86 (s, 6H, 2×OMe), 2.43 (s, 3H).

Example 34 Preparation of2-Dimethylaminomethylene-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

To a stirred solution of2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxy-benzo[b]furan(Example 33) (25 mg, 0.051 mmol) in dry THF (0.5 mL) was added solutionof dimethylamine (0.5 mL, excess, 2M solution in THF) and the mixturewas stirred for 6 hours at room temperature (tlc). The solvent wasdistilled and the crude was purified over silica gel to afford the titlecompound as a light yellow solid (15 mg, 71%). ¹H NMR (300 MHz, CDCl₃)δ-7.14 (s, 2H, benzoyl Hs), 6.85 (s, 2H, Ar—Hs), 3.93 (s, 3H, OMe), 3.92(s, 3H, OMe), 3.81 (s, 6H, 2×OMe), 3.75 (s, 2H), 2.31 (s, 6H).

Example 35 Preparation of2-(1H-Imidazol-1-yl)methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

To a stirred suspension of2-bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-acetoxy-benzo[b]furan(Example 33) (35 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.15mmol) in dry acetonitrile (1.5 mL) was added imidazole (19 mg, 0.28mmol) and the reaction mixture was stirred for overnight (tlc). Thesolvent was distilled under vacuum and the crude was taken in ethylacetate, filleted and purified over silica gel plate to afford the titlecompound as a light yellow solid (6 mg, 19%). ¹H NMR (300 MHz, CDCl₃)δ-7.66 (s, 1H), 7.19 (s, 1H), 7.09 (s, 2H, benzoyl Hs), 7.07 (s, 1H),6.85 (d, J=8.63 Hz, 1H), 6.74 (d, J=8.63 Hz, 1H), 5.37 (s, 2H), 4.00 (s,3H, OMe), 3.95 (s, 3H, OMe), 3.79 (s, 6H, 2×OMe).

Example 36 Preparation of2-(5-amino-2H-tetrazol-2-yl)-methyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

When imidazole was replaced with aminotetrazole as in the above examplethe identical procedure afforded the title compound as a light yellowsolid (2 mg, 9%). ¹H NMR (300 MHz, CDCl₃) 7.20 (s, 2H, benzoyl Hs), 6.86(d, J=8.71 Hz, 1H), 6.72 (d, J=8.48 Hz, 1H), 6.01 (s, 2H), 5.61 (s, 2H),3.98 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.81 (s, 6H, 2×OMe).

Example 37 Preparation of2-(4-Methylpiperazin-1-yl)methyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

To a stirred solution of2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxybenzo[b]furan(Example 33) (50 mg, 0.10 mmol) in dry THF (2 mL) at room temperaturewas added N-methylpiprazine (24 μL, 0.22 mmol) and the mixture wasstirred for 2 hours and then added solution of dimethylamine (0.2 mL, 2Msolution in THF, excess) and stirred for 4 hours. The solvent wasdistilled and the crude was purified over silica gel column and theproduct was crystallized from acetonitrile to afford the title compoundas a light yellow crystalline solid (22 mg, 46%). ¹H NMR (300 MHz,CDCl₃) δ 7.12 (s, 2H, benzoyl Hs), 6.89 (d, J=8.58 Hz, 1H), 6.85 (d,J=8.58 Hz, 1H), 3.93 (s, 6H, 2×OMe), 3.82 (s, 6H, 2×OMe), 2.57 (b, 4H),2.39 (b, 4H), 2.23 (s, 3H, NMe).

Example 38 Preparation of7-isopropoxy-6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H-indole

Step A: 2-isopropoxy-3-methoxyaniline

To a solution of 2-nitroguaiacol (Thompson, M. J.; Zeegerers, P. J.Tetrahedron, 1990, 46, 2661; 0.5062 g; 3 mmol) in anhydrous DMF (5 ml)K₂CO₃ (0.41 g; 3 mmol) was added and resulting mixture was stirred for15 min under reduced pressure and saturated with N₂. To it,2-bromopropane (1 ml; 10.6 mmol) was added and the reaction flask wassealed with septum and stirred overnight at 55° C. After evaporation ofDMF under reduced pressure the residue was partitioned between diethylether (20 ml) and water (10 ml). The organic phase was washed with 2%aq. KOH (5 ml), brine, dried over anhydrous MgSO₄, filtered off andfiltrate evaporated to dryness. The residue was dissolved in smallvolume of CH₂Cl₂ and filtered through short column with SiO₂, which waseluded with fresh CH₂Cl₂. The combined filtrates were evaporated todryness under reduced pressure to give2-isopropoxy-3-methoxynitrobenzene (0.62 g; 98% yield) as creamy syrup.¹H-NMR (CDCl₃) 1.26 (d, 6H, J=6.17 Hz); 3.87 (s, 3H); 4.61 (m, 1H,J=6.17 Hz); 7.06 (m, 2H); 7.26 (m, 1H). This was dissolved in ethanol(30 ml) and the resulting mixture was degassed under reduced pressure.To it 10% Pd on carbon (0.22 g) was added and the mixture was saturatedwith H₂ and stirred for 5 h under the balloon pressure of H₂. Thecatalyst was removed by filtration through Celite. The filtrate wasevaporated to dryness to give the title compound (0.702 g; 92.5% yield)as colourless oil. ¹H-NMR (CDCl₃) 1.28 (d, 6H, J=6.19 Hz); 3.7 broad s,2H); 3.79 (s, 3H); 4.45 (m, 1H, J=6.19 Hz); 6.2-6.78 (m, 2H); 6.8 (m,1H).

Step B: 6-iodo-2-isopropoxy-3-methoxy-N-trifluoroacetylaniline

To a suspension of CF₃CO₂Ag and the product of Step A (0.702 g; 3.88mmol) in CH₂Cl₂ (30 ml) I₂ (0.99 g: 3.88 mmol) was added at 0° C. Afterstirring for 30 min at 0° C. the reaction mixture was filtered throughCelite and filtrate washed with 5% aq Na₂S₂O₅ solution (2×15 ml), driedover anhydrous MgSO₄, filtered off and filtrate evaporated to dryness togive the crude 2-iodo-2-isopropoxy-3-methoxyaniline, which was usedwithout further purification. This (0.84 g; 2.7 mmol) was dissolved indry pyridine (5 ml) and to it trifluoroacetic anhydride (0.41 ml; 2.9mmol) was added at room temperature. The resulting mixture was stirredfor 2 h at room temperature and evaporated to dryness under reducedpressure. The residue was purified by flash column chromatography (SiO₂,hexane/ethyl acetate, 8:2) to give the title compound (0.675 g; 61%yield) as a colourless crystals. ¹H-NMR (CDCl₃) 1.21 (d, 6H, J=6.16 Hz);3.83 (s, 3H); 4.51 (m, 1H, J=6.16 Hz); 6.69 (d, 1H, J=8.86 Hz); 7.51 (d,1H, d, 1H, J=8.86 Hz); 7.67 (broad s, 1H).

Step C: 2-isopropoxy-3-methoxy-6-(prop-1-ynyl)-N-trifluoroacetylaniline

A mixture of the product of Step B (0.275 g; 0.681 mmol), Cl₂Pd(PPh₃)₂(0.058 g; 0.083 mmol); CuI (0.025 g; 0.13 mmol), anhydrousN,N-diisopropyl ethylamine (1 ml) in anhydrous DMF (5 ml) was cooled to−40° C., degassed under reduced pressure and saturated with dry N₂. Toit, propyne gas (0.5 g; 12.4 mmol) was added at −40° C. The reactionflask was sealed with septum and allowed to warm up to room temperatureand stirred overnight at room temperature than evaporated to drynessunder reduced pressure. The residue was purified by flash columnchromatography (SiO₂, hexane/ethyl acetate, 8:2) to give the titlecompound (0.171 g; 79% yield) as creamy solid. ¹H-NMR (CDCl₃) 1.21 (d,6H, J=6.16 Hz); 2.00 (s, 3H); 3.86 (s, 3H); 4.43 (m, 1H, J=6.16 Hz);6.79 (d, 1H, J=8.67 Hz); 7.14 (d, 1H, J=8.67 Hz); 7.72 (broad s, 1H).

Step D:7-isopropoxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H-indole

A mixture of the product of Step C (0.171 g; 0.54 mmol),3,4,5-trimethoxyphenyl iodide (0.191 g; 0.65 mmol), Cl₂Pd(PPh₃)₂ (0.044g; 0.063 mmol); dry K₂CO₃ (0.23 g; 1.62 mmol in anhydrous DMF (5 ml) wasdegassed under reduced pressure and saturated with CO gas. The resultingmixture was vigorously stirred overnight at room temperature under COballoon, then diluted to 50 ml with ethyl acetate and washed with water(3×15 ml), brine and dried over anhydrous MgSO₄, filtered off andfiltrate evaporated to dryness. The residue was purified by flash columnchromatography (SiO₂ CH₂Cl₂/ethyl acetate, 9:1) to give the titlecompound (0.143 g; 64% yield) as a yellow solid. ¹H-NMR (CDCl₃) 1.27 (d,6H, J=6.14 Hz); 2.51 (s, 3H); 3.79 (s, 6H); 3.85 (s, 3H); 3.90 (s, 3H);4.69 (m, 1H, J=6.14 Hz): 6.76 (d, 1H, J=8.75 Hz); 7.04 (s, 2H); 7.11 (d,1H, J=8.75 Hz); 8.83 (broad m, 1H).

Example 39 Preparation of7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H-indole

To a solution of the product of Step D of above Example 38 (0.055 g;0.133 mmol) in anhydrous CH₂Cl₂, TiCl₄ (0.04 ml; 0.36 mmol) was added at0° C. The resulting mixture was stirred for 1 h and quenched by additionof H₂O (3 ml). The two-phase mixture was diluted to 15 ml with CH₂Cl₂and organic phase separated, dried over anhydrous MgSO₄, filtered offand filtrate evaporated to dryness. The residue was purified by flashcolumn chromatography (SiO₂; CH₂Cl₂/ethyl acetate, 9:1) to give thetitle compound (0.0365 g; 74% yield) as a yellow solid. ¹H-NMR (CDCl₃)2.54 (s, 3H); 3.81 (s, 6H); 3.88 (s, 3H); 3.92 (s, 3H), 5.65 (s, 1H);6.77 (d, 1H, J=8.71 Hz); 6.96 (d, 1H, J=8.71 Hz); 7.05 (s, 2H); 8.48 (s,1H).

Example 40 Preparation of3-(3,5-Dimethoxy-4-hydroxybenzoyl)-7-hydroxy-6-methoxy-2-methyl-1H-indole

The title compound (0.003 g; 6.3% yield) was obtained as a by-productfrom the purification of Example 39, as a creamy solid. ¹H-NMR (CDCl₃)2.58 (s, 3H); 3.85 (s, 6H); 3.9 (s, 3H); 5.67 (s, 1H); 5.86 (s, 1H) 6.75(d, 1H, J=8.7 Hz); 6.94 (d, 1H, J=8.71 Hz); 7.12 (s, 2H); 8.47 (s, 1H).

Example 41 Preparation of6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-7-tosyloxy-benzo[b]thiophene

Step A: Benzyl 2-iodo-6-isopropoxy-5-methoxyphenyl sulfide

A mixture of the product of Step B, Example 37 (0.4 g; 1.16 mmol) in 20%solution of hydrazine in iPrOH (10 ml) was refluxed for 4 h under N₂ andevaporated to dryness under reduced pressure. The residue was diluted to30 ml with diethyl ether, washed with H₂O (2×5 ml), brine (10 ml), driedover anhydrous MgSO₄, filtered and filtrate evaporated to dryness underreduced pressure to give 2-amino-3-isopropoxy-4-methoxy-iodobenzene(0.256 g; 71%) which was used without further purification. This wasstirred with the mixture of H₂O (1.2 ml) and 48% HBF₄ (0.8 ml) for 15min at room temperature. The resulting mixture was cooled to 0° C. andNaNO₂ (0.069 g; 1 mmol) in H₂O (0.5 ml) was added to it drop wise at 0°C. during 10 min with stirring. This was allowed to warm up to roomtemperature and the precipitate filtered off, washed with H₂O (1 ml),diethyl ether (1 ml) and dried in vacuo to give relevant diazoniumintermediate (0.23 g; 69%). This was added portionwise to a solution ofEtOC(S)SK (0.1 g; 0.62 mmol) in acetone (1.5 ml) at 0° C. during 10 min.After stirring for 30 min at 0° C., the stirring was continued for 45min at room temperature and the mixture was evaporated to dryness underreduced pressure. The residue was diluted to 15 ml with diethyl ether,washed with H₂O (10 ml), 2% KOH (2 ml), brine, dried over anhydrousMgSO₄, filtered and filtrate evaporated to dryness under reducedpressure. The residue was dissolved in MeOH (2 ml) and KOH (0.3 g; 5.3mmol) was added. After stirring for 1 h at room temperature the mixturewas evaporated to dryness under reduced pressure and the residuepartitioned between CH₂Cl₂ (2 ml) and H₂O (1 ml). Benzyl bromide (0.14ml; 0.96 mmol) and n-Bu₄NHSO₄ (0.05 g;) was added to it, and theresulting mixture was vigorously stirred for 1 h, diluted to 15 ml withCH₂Cl₂. The organic phase was dried over anhydrous MgSO₄, filtered andfiltrate evaporated to dryness under reduced pressure. The residue waspurified by flash column chromatography (SiO₂; hexane/ethyl acetate9.5:0.5) to give pure title compound (0.123 g; 52%) as colourless syrup.¹H-NMR (CDCl₃) 1.33 (d, 6H, J=6.18 Hz); 3.8 (s, 3H); 4.12 (s, 2H); 4.62(m, 1H, J=6.18 Hz); 6.58 (d, 1H, J=8.71 Hz); 7.14-7.32 (m, 5H); 7.5 (d,1H, J=8.71 Hz).

Step B: Benzyl 6-isopropoxy-5-methoxy-2-(prop-1-ynyl)phenyl sulfide

A mixture of the product of Step A (0.123 g; 0.296 mmol), Cl₂Pd(PPh₃)₂(0.040 g; 0.057 mmol), CuI (0.014 g; 0.073 mmol) in anhydroustriethylamine (3 ml) was cooled to −40° C., degassed under reducedpressure and saturated with dry N₂. The propyne gas (0.45 g; 11.2 mmol)was added to it at −40° C. The reaction flask was sealed with septum andallowed to warm up to room temperature and stirred for 3 h at roomtemperature and diluted to 20 ml with diethyl ether and solidprecipitated, filtered off. The filtrate was evaporated to dryness underreduced pressure and the residue, purified by flash columnchromatography (SiO₂, hexane, hexane/ethyl acetate, 9:1) to give thetitle compound (0.065 g; 67% yield) as colourless syrup. ¹H-NMR (CDCl₃)1.26 (d, 6H, J=6.17 Hz); 2.09 (s, 3H); 3.79 (s, 3H); 4.2 (s, 2H); 4.44(m, 1H, J=6.17 Hz); 6.73 (d, 1H, J=8.53 Hz); 7.12 (d, 1H, J=8.53 Hz);7.15-7.4 (m, 5H).

Step C: 3-Iodo-7-isopropoxy-6-methoxy-2-methylbenzo[b]thiophene

When the product of Step B was substituted for benzyl5-methoxy-2-(prop-1-ynyl)phenyl sulfide in Step B of Comparator D, theidentical process provided the title compound in 67% yield, as a heavycolourless syrup. ¹H-NMR (CDCl₃) 1.32 (d, 6H, J=6.14 Hz); 2.53 (s, 3H);3.9 (s, 3H); 4.69 (m, 1H, J=6.14 Hz); 7.07 (d, 1H, J=8.66 Hz); 7.28 (d,1H, J=8.66 Hz).

Step D: 7-Isopropoxy-6-methoxy-2-methylbenzo[b]thiophene

When 3-iodo-7-isopropoxy-6-methoxy-2-methylbenzo[b]thiophene wassubstituted for 3-iodo-6-methoxy-2-methylbenzo[b]thiophene in Step C ofComparator D, the identical process provided the title compound in 67%yield, as a heavy colourless syrup. ¹H-NMR (CDCl₃) 1.33 (d, 6H, J=6.14Hz); 2.51 (s, 3H); 3.88 (s, 3H); 4.69 (m, 1H, J=6.14 Hz); 6.84 (, 1H);6.96 (d, 1H, J=8.51 Hz); 7.27 (d, 1H, J=8.51 Hz).

Step E: 6-methoxy-2-methyl-7-tosyloxy-benzo[b]thiophene

To a mixture of the product of Step D (0.033 g; 0.0941 mmol) in CH₂Cl₂(1 ml) TiCl4 (0.02 ml; 0.182 mmol) was added at room temperature underN₂. After stirring for 10 min at room temperature, the mixture wasdiluted to 15 ml with CH₂Cl₂ and quenched with H₂O (5 ml) and theorganic phase was dried over anhydrous MgSO₄, filtered and filtrateevaporated to dryness under reduced pressure to give7-hydroxy-6-methoxy-2-methyl-benzo[b]thiophene (0.0256 g; 100%). Thiswas diluted to 1.ml with CH₂Cl₂ and tosyl chloride (0.03 g; 0.158 mmol),followed by triethylamine 0.022 ml; 0.158 mmol) of were added to it. Theresulting mixture was stirred for 1 h at room temperature, washed withH₂O, dried over anhydrous MgSO₄, filtered and filtrate evaporated todryness under reduced pressure. The residue was purified bycrystallization from hexane/ethyl acetate mixture (9.5:0.5) to give thetitle compound (0.035 g; 68%), as creamy crystals. ¹H-NMR (CDCl₃) 2.45(s, 3H); 2.48 (s, 3H); 3.63 (s, 3H); 6.83 (s, 1H); 7.32 (d, 2H, J=8.27Hz); 7.43 (d, 1H, J=8.62 Hz), 7.87 (d, 2H, J=8.62 Hz).

Step F:6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-7-tosyloxy-benzo[b]thiophene

When 6-methoxy-2-methyl-7-tosyloxy-benzo[b]thiophene was substituted for6-methoxy-2-methylbenzo[b]thiophene in Step D of Comparator C, theidentical process provided the title compound in 68% yield, as a heavycolourless syrup. ¹H-NMR (CDCl₃) 2.42 (s, 3H); 2.46 (s, 3H); 3.61 (s,3H); 3.82 (s, 6H); 3.93 (s, 3H): 6.91 (d, 1H, J=8.87 Hz); 7.09 (s, 2H);7.34 (d, 2H, J=8.19 Hz), 7.43 (d, 1H, J=8.87 Hz); 7.88 (d, 2H, J=8.19Hz).

Example 42 Preparation of7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene

A mixture of the product of Example 41 (0.035 g; 0.00645 mmol) in THF(0.5 ml) and 1% NaOH in MeOH (0.52 ml; 0.0129 mmol) was stirredovernight at 30° C. under N₂ and acidified with the drop of CF₃CO₂H.This was evaporated to dryness and diluted to 15 ml with diethyl ether,washed with 0.1 M HCl (2 ml), 5% NaHCO₃ (2 ml), brine, dried overanhydrous MgSO₄, filtered and filtrate evaporated to dryness underreduced pressure. The residue was purified by flash columnchromatography (SiO₂, CH₂Cl₂) to give pure title compound (0.007 g;28%), as a colourless crystals. ¹H-NMR (CDCl₃) 2.47 (s, 3H); 3.83 (s,6H); 3.92 (s, 6H); 5.94 (s, 1H); 6.93 (d, 1H, J=8.69 Hz); 7.05 (d, 1H,J=8.69 Hz); 7.1 (s, 2H).

Example 43 Preparation of 2-[(N-Methyl-2-amino-aceticacid methylester)-methenyl)-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

A mixture of2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxy-benzo[b]furanExample 33 (185 mg, 0.38 mmol) and sarcosine-methyl-ester-hydrochloride(156 mg, 1.11 mmol) in a mixture of dry DMF:DIEA (3 mL:0.5 mL) wasstirred at room temperature for overnight (tlc). The solvent wasdistilled and the crude residue was dissolved in THF (1 mL) anddimethylamine (0.5 mL, excess) was added to it and stirred for 2 hoursat room temperature. The solvent was distilled and the crude product waspurified over silica gel column to gave the product as a light yellowpaste (132 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ-7.13 (s, 2H, benzoyl Hs),6.85 (s, 2H, Ar—Hs), 4.02 (s, 2H), 3.93 (s, 6H, 2×OMe), 3.81 (s, 6H,2×OMe), 3.64 (s, 3H, OMe), 3.88 (s, 2H), 2.45 (s, 3H, NMe).

Example 44 Preparation of2-[(N-Methyl-2-amino-aceticacid)-methenyl)-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

The ester Example 43 above (120 mg, 0.25 mmol) was dissolved inTHF:water (3 mL; 2:1), solution of LiOH (12 mg, 0.5 mmol in 0.25 mL ofwater) was added to it and the mixture was stirred for 3 hours at roomtemperature. The solvent was distilled to 1 mL and diluted withdichloromethane (10 mL). Tri-fluoro acetic acid (40 μL, 0.52 mmol) wasadded when the compound went into dichloromethane making the solutionyellow colored. The organic layer was separated, dried over magnesiumsulphate and solvent was distilled to gave the product as light yellowsolid which was crystallized from hexane/DCM to gave the dirty coloredsolid (66 mg, 57%). ¹H NMR (300 MHz, CDCl₃) δ-7.10 (s, 2H, benzoyl Hs),7.07 (d, J=8.62 Hz, 1H), 6.63 (d, J=8.58 Hz, 1H), 4.69 (s, 2H), 4.00 (s,2H), 3.92 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.76 (s, 6H, 2×OMe), 2.96 (s,3H, NMe).

Example 45 Preparation of2-N-(Aminoethanesulphonamide)-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

When benzyl-amine was substituted with aminoethane sulphonamide. HCl asin Example 19 step 1 the identical procedure afforded the title compoundas a yellow solid (25 mg, 25%) along with2-amino-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-hydroxy-benzo[b]furan(Example 1927 mg, 35%). ¹H NMR (300 MHz, CDCl₃) δ-9.21 (bs, 1H, NH),6.94 (s, 2H, benzoyl Hs), 6.62 (d, J=8.61 Hz, 1H), 6.51 (d, J=8.47 Hz,1H), 5.1 (b, 2H), 4.15 (q, 2H, J=12.32, 6.38 Hz), 3.91 (s, 3H, OMe),3.86 (s, 3H, OMe), 3.83 (s, 6H, 2×OMe), 3.54 (t, 2H, J=6.18 Hz).

Example 46 Preparation of3-(4-Hydroxy-3,5-di-methoxy-benzoyl)-7-hydroxy-6-methoxy-2-Methyl-benzo[b]furan

2-Methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy-benzo[b]furanExample 11 (100 mg, 0.27 mmol) was dissolved in dry dichloromethane (5mL) and solid aluminium trichloride (72 mg, 0.54 mmol) was added to it.The mixture was stirred for 2 hours when additional amount of aluminiumtrichloride (72 mg, 0.54 mmol) was added and the stirring was continuedfor 2 more hours (tlc). The reaction was quenched with saturatedsolution of ammonium chloride and diluted with DCM (20 mL) the organiclayer was separated and washed with water, dried over magnesium sulphateand solvent was distilled to gave the crude product which was purifiedover silica gel column. The compound was crystallized from methanol togave the product as white solid. (42 mg, 44%). ¹H NMR (300 MHz, CDCl₃) δ7.16 (s, 2H, benzoyl Hs), 6.91 (d, J=8.58 Hz, 1H), 6.83 (d, J=8.58 Hz,1H), 5.94 (s, 1H, OH), 5.68 (s, 1H, OH), 3.91 (s, 3H, OMe), 3.87 (s, 6H,2×OMe), 2.54 (s, 3H, Me).

Example 47 Further Alternative Method for the Preparation of2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furanby Multi-component Coupling Step 1:2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan

To a stirred solution of 2-isopropoxy-3-methoxy-6-iodophenol (308 mg,1.00 mmol) in dry tetrahydrofuran (2 mL) was added dropwise a solutionof 1-propynyl magnesium bromide (5, 6 mL, 3 mmol, 0.5 M solution in THF)at 0° C. under nitrogen. Dichloro-bis-triphenylphosphine palladiumcatalyst (40 mg, 0.06 mmol) was added and the reaction mixture washeated to 70° C. for 3 hours (tlc). The solvent was removed under vacuumand the residue was dried under vacuum. Dry dimethylsulfoxide (8 mL) wasadded and the nitrogen atmosphere was replaced with carbon monoxide.3,4,5-Trimethoxyiodobenzene 6 (310 mg 1.05 mmol) was added and thereaction mixture was stirred at 90° C. for 17 hours and then quenchedwith saturated ammonium chloride solution and extracted with ethylacetate (2×25 mL). The organic layer was washed with water and driedover magnesium sulphate. The crude product was purified by flashchromatography (silica gel, eluent=hexane/diethyl ether; 8:2-7:3) toafford the title compound as a creamy white solid. The product wascrystallized from methanol. Yield—290 mg, 70%; ¹H NMR (300 MHz, CDCl₃)δ-7.10 (s, 2H, benzoyl Hs), 7.07 (d, 1H), 6.85 (d, 1H, J=8.57),4.74-4.68 (m, 1H), 3.93 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.83 (s, 6H,2×OMe), 2.52 (s, 3H, Me), 1.37 (d, 6H, J=6.18 Hz).

Step 2:2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan

To a stirred solution of2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan(30 mg, 0.073 mmol) at 0° C. in dry dichloromethane (1 mL) was addedboron trichloride solution (1M solution in DCM, 73 μL, 0.073 mmol) andreaction mixture was warmed to room temperature and the stirring wascontinued for 2 hours (tlc). The reaction mixture was quenched withsaturated ammonium chloride solution and diluted with dichloromethane (5mL). the organic layer was separated and dried over magnesium sulphate.The solvent was distilled to gave the crude product as off white coloredcrystalline solid which was re-crystallized from methanol to gave theproduct as white crystalline material. Yield—25 mg, 93% (Note 1). ¹H NMR(300 MHz, CDCl₃) δ-7.09 (s, 2H, benzoyl Hs), 6.93 (d, 1H, J=8.54 Hz),6.83 (d, 1H, J=8.56 Hz), 5.70 (bs, 1H, OH), 3.93 (s, 3H, OMe), 3.92 (s,3H, OMe), 3.83 (s, 6H, 2×OMe), 2.54 (s, 3H, 2-Me).

Note: A similar reaction when scaled-up with2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan(1.25 gm) and boron trichloride solution (1M solution in DCM, 3.1 mL)gave the title compound (930 mg, 83%).

Example 48 Further Alternative Method for the Preparation of2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furanby Friedel-Crafts Acylation Step 1:2-Methyl-7-hydroxy-6-methoxy-benzo[b]furan

The solution of 3-iodo-6-methoxy-1,2-phenylene diacetate [(prepared bythe iodination of diacetylglucinol with I₂ and CF₃CO₂Ag (1 gm, 2.86mmol) ¹H NMR (300 MHz, CDCl₃) δ-7.59 (d, 1H, J=8.88 Hz), 6.66 (d, 1H,J=8.94 Hz), 3.81 (s, 3H, OMe), 2.34 (s, 3H), 2.27 (s, 3H)] in a mixtureof DMF/diisopropylethylamine (12 mL:1.5 mL) was degassed with nitrogengas and the solution was cooled to −40° C. Propyne gas (app wt. 3 gm,excess) was passed through this stirred solution over a period of 30minutes. To this mixture was added Pd(PPh₃)₂Cl₂ (120 mg) followed by theaddition of the copper (I) iodide (40 mg) and the mixture was allowed tocome to room temperature and stirred for additional 40 hours (tlc). Tothis solution was added di-methyl-amine (4 mL, 1M solution in THF) andthe mixture was stirred for another 18 hours at room temperature. Thesolvent was distilled in vacuum and the residue was taken inethyl-acetate (50 mL). The organic layer was washed with water, driedover magnesium sulphate and the solvent was distilled to give the crudecompound which was characterized as such by NMR. ¹H NMR (300 MHz, CDCl₃:D₂O exchange) δ-6.82 (d, 1H, J=8.58 Hz), 6.39 (d, 1H, J=8.60 Hz), 3.85(s, 3H, OMe), 2.08 (s, 3H, Me).

The above crude product was dissolved in dry THF (6 mL) and TBAF (1 mL,1M solution in THF) was added to it and the mixture was stirred withrefluxing for 8 hours. Solvent was distilled in vacuum and the residuewas dissolved in DCM (20 mL) and washed with 1M HCl solution. Theorganic layer was separated, dried over magnesium sulphate and the crudewas purified over silica gel column (eluent=Hexane:di-ethyl-ether; 100:0to 60:40) to give the pure product (17) as light cream paste (390 mg,77%). ¹H NMR (300 MHz, CDCl₃: D₂O exchange) δ-6.89 (d, 1H, J=8.37 Hz),6.39 (d, 1H, J=8.38 Hz), 6.26 (s, 1H, 3H), 5.61 (bs, 1H, OH), 3.91 (s,3H, OMe), 2.42 (s, 3H, Me).

Step 2: 2-Methyl-6-methoxy-7-(4-toluoylsulphonate)-benzo[b]furan

2-Methyl-7-hydroxy-6-methoxy-benzo[b]furan, from Step 1 above, (180 mg,1 mmol) was dissolved in dry pyridine (2 mL) andp-toulene-sulphonyl-chloride (228 mg, 1.2 mmol) and the mixture wasstirred at 80° C. for 6 hours. Solvent was distilled and the crude wastaken in ethyl-acetate (15 mL) and washed with water. The organic layerwas dried over the magnesium sulphate and solvent was distilled to gavethe crude which was purified over silica gel column(eluent=Hexane:ethyl-acetate:dieth-ylether; 80:0:20 to 70:10:20) to gavethe compound (3, 128 mg, 39%+starting material) as light yellow pastesolidify on standing at room temperature. ¹H NMR (300 MHz, CDCl₃: D₂Oexchange) δ-7.84 (d, 2H, J=7.71 Hz), 7.29 (d, 2H, J=8.05 Hz), 7.21 (d,1H, J=8.49 Hz), 6.78 (d, 1H, J=8.47 Hz), 6.22 (s, 1H, 3H), 3.69 (s, 3H,OMe), 2.42 (s, 3H, Me), 2.25 (s, 3H, Me).

Step 3:2-Methyl-3(3,4,5-trimethoxybenzoyl)-6-methoxy-7-(4-methyl-benzene-sulphonate)-benzo[b]furan

2-Methyl-6-methoxy-7-(4-methylbenzenesulphonate)-benzo[b]furan, fromStep 2 above (65 mg, 0.2 mmol) was dissolved in dry dichloromethane (2mL) and 3,4,5-trimethoxy-benzoyl-chloride (55 mg, 0.24 mmol) followed bythe addition of tin(II) chloride (28 μL, 0.24 mmol) and the mixture wasstirred at reflux for 8 hours, more acid chloride (20 mg) and reactionwas continued for another 6 hours (tlc). Reaction was diluted withdichloromethane (15 mL) and organic layer was washed with sodiumbicarbonate solution. The organic layer was separated, dried over themagnesium sulphate and solvent was distilled to gave the crude which waspurified over silica gel column (eluent=Hexane:diethyl ether; 80:0 to70:30) to gave the product (70 mg, 68%) as light yellow solid. ¹H NMR(300 MHz, CDCl₃: D₂O exchange) δ 7.86 (d, 2H, J=8.31 Hz), 7.34-7.22(overlapping doublets, 3H), 7.06 (s, 2H, benzoyl H), 6.83 (d, 1H, J=8.73Hz), 3.93 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.68 (s, 3H, OMe), 2.46 (s,3H, Me), 2.39 (s, 3H, Me).

Note: The same reaction was run by using 240 mg of starting benzofuran,acid chloride 254 mg, tin (IV) chloride 101 uL. (Yield=297 mg, 78%).

Step 4:2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b]furan(Example 11)

2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-(4-methyl-benzene-sulphonate)-benzo[b]furan,from Step 3 above, was dissolved in a mixture of solvent (THF/MeOH; 4mL:10 mL) and sodium hydroxide (32 mg) was added to it and the mixturewas stirred with refluxing for 6 hours. The solvent was distilled andthe crude was taken in dichloromethane (20 mL) and washed with water (20mL×2). The organic layer was separated and dried over magnesium sulphateand the solvent was distilled. The crude product was purified oversilica gel column to give the product (150 mg, 76%).

Example 49 Alternative Method for the Preparation of Example 29 UsingPOCl₃

To a solution of freshly distilled POCl₃ (0.125 ml; 1.34 mmol) inanhydrous CH₂Cl₂ (1 ml) a mixture of Example 11 (0.2 g; 0.54 mmol) andtriethylamine (0.12 ml; 0.86 mmol) in anhydrous CH₂Cl₂ (1 ml) was addeddropwise at −5 to 0° C. under N₂ with stirring. After stirring for 10minutes at 0° C., the mixture was evaporated to dryness under reducedpressure. The residue was suspended in anhydrous toluene (2 ml), stirredfor 5 minutes at room temperature and evaporated to dryness underreduced pressure. The residue was kept in vacuo for 30 minutes and thenresuspended in acetonitrile (2 ml). This was added at once to 0.5 Maqueous NaOH (5 ml). The resulting mixture was evaporated to drynessunder reduced pressure and the residue was suspended in water (2.ml).After adjusting the pH of the solution to ˜10 with 0.5 M NaOH, theresulting solution was filtered through Whatman glass microfibre filterto remove any traces of solid material. The filtrate was concentrated toabout 0.5 ml and acidified to pH ˜1 with concentrated HCl. To facilitatethe removal of water and the excess of HCl the mixture was repeatedlydiluted to 5 ml with acetonitrile and evaporated to dryness (×3),followed by dilution with CH₂Cl₂ and evaporation. The residue formed,was kept in vacuo for 30 minutes and suspended in methanol/CH₂Cl₂mixture (5:95; 10 ml) (NOTE 2) and insoluble NaCl was filtered off. Thefiltrate was evaporated to dryness and the crystalline residue waswashed with hexane/CH₂Cl₂ mixture (1:1; 10 ml) and dried to give freeacid as a slightly creamy solid (0.209 g; 87%). ¹HNMR (CDCl₃/CD₃OD 1:1)2.5 (s, 3H); 3.29 (m, CD₃OD); 3.81 (s, 6H); 3.87 (s, 3H); 3.88 (s, 3H);4.6 (s, HDO); 6.91 (d, 1H, J=8.7 Hz); 7.08 (s, 2H); 7.12 (d, 1H, J=8.7Hz); 7.55 (s, CDCl₃); LC, retention time=1.19 min (+99%); MS 452.8(MH₂+1). The free acid was suspended in methanol (2 ml) and the pH ofthe resulting suspension was adjusted to ˜10 by addition of 0.5 M NaOH.During this process the mixture gradually become homogenous. This wasconcentrated to about 1 ml and the product was precipitated by theaddition of acetonitrile (10 ml). The solid was washed with freshacetonitrile, anhydrous ethyl ether and dried in vacuo until constantmass to give 0.215 g of pure title compound (94% yield) as a creamysolid. ¹HNMR (D₂O) 7.09 (s, 2H), 7.02 (d, 1H, J=8.68 Hz), 6.91 (d, 1H,J=8.68 Hz), 4.66 (HDO), 3.8 (s, 3H), 3.79 (s, 3H), 3.75 (s, 6H), 2.36(s, 3H). LC, retention time=1.19 (+99%). MS 452.8 (MH₂−2Na+1). Anal.Calculated for C₂₀H₁₉Na₂O₁₀P×0.5H₂O: Na, 9.10%; P, 6.13%. Found Na,9.09%; P, 9.26%.

Example 50 Comparator F Preparation of6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H-indole

A mixture of 2-iodo-5-methoxy-N-trifloroacetylaniline (Flynn et al, J.Med. Chem., 2002, 45(12), 2670; 0.508 g; 1.5 mmol), Cl₂Pd(PPh₃)₂ (0.102g; 0.145 mmol); CuI (0.016 g; 0.085 mmol), anhydrous N,N-diisopropylethylamine (1 ml) in anhydrous DMF (10 ml) was cooled to −40° C.,degassed under reduced pressure and saturated with dry N₂. The propynegas (0.53 g; 13.3 mmol) was added to it at −40° C. The reaction flaskwas sealed with septum and allowed to warm up to room temperature andstirred for 3 h. After removal of excess of propyne under reducedpressure 3,4,5-trimethoxyphenyl iodide (0.5 g; 1.7 mmol) was added toit, followed by dry K₂CO₃ (0.621 g; 4.5 mmol). The resulting mixture wasdegassed in vacuo and saturated with CO gas and stirred for 3 h under COballoon pressure. The mixture was diluted to 50 ml with diethyl ether,washed with H₂O (2×15 ml), brine (10 ml), dried over anhydrous MgSO₄,filtered and filtrate evaporated to dryness under reduced pressure. Theresidue was purified by flash column chromatography (SiO₂; CH₂Cl₂) togive pure title compound (0.295 g; 55%) as a yellow crystals:

¹H-NMR (CDCl₃) 2.52 (s, 3H,); 3.8 (m, 9H); 3.91 (s, 3H); 6.73 (dd, 1H,J=2.22, 8.75 Hz); 6.79 (d, 1H, J=2.22 Hz); 7.06 (s, 2H); 7.35 (d, 1H,J=8.75 Hz); 8.6 (broad s, 1H, NH).

Example 51 Comparator G Preparation of6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene

Step A: Benzyl 5-methoxy-2-(prop-1-ynyl)phenyl sulfide

When benzyl 2-iodo-5-methoxyphenyl sulfide (Flynn et al, Org. Lett.2001, 3(5), 651) was substituted for6-iodo-2-isopropoxy-3-methoxy-N-trifluoroacetylaniline in Step C ofExample 38 and reaction time was extended to 72 h, the similar processprovided the title compound in 69% yield as a creamy solid. ¹H-NMR(CDCl₃) 2.1 (s, 2H); 3.7 (s, 3H); 4.17 (s, 2H); 6.61 (dd, 1H, J=2.53,8.5 Hz); 6.72 (d, 1H, J=2.53 Hz); 7.2-7.33 (m, 5H); 7.38 (d, 1H, J=8.5Hz).

Step B: 3-Iodo-6-methoxy-2-methylbenzo[b]thiophene

To a solution of the product of Step A (0.156 g; 0.58 mmol) in CH₂Cl₂ 1ml) I₂ (0.147 g: 0.58 mmol) was added and the mixture was stirred for 1h at room temperature, then washed with 5% aq Na₂S₂O₅ solution (2×5 ml),dried over anhydrous MgSO₄, filtered off and filtrate evaporated todryness to give the crude 2-iodo-2-isopropoxy-3-methoxyaniline, whichwas purified by flash column chromatography (SiO₂, hexane, hexane/ethylacetate 9.5:0.5) to give the title compound (0.0863 g; 47%) ascolourless syrup. ¹H-NMR (CDCl₃) 2.58 (s, 3H); 3.85 (s, 3H); 6.99 (dd,1H, J=2.33, 8.8 Hz); 7.19 (d, 1H, J=2.33 Hz); 7.51 (d, 1H, J=8.8 Hz).

Step C: 6-Methoxy-2-methylbenzo[b]thiophene

t-BuLi (1.7 M in pentane; 0.32 ml; 0.54 mmol) was added to a solution ofthe 3-iodo-6-methoxy-2-methylbenzo[b]thiophene (0.0863 g; 0.27 mmol) inanhydrous THF (2.5 ml) at −78° C. under N₂. The mixture was allowed towarm up to 0° C. and quenched by the addition of saturated NH₄Cl (1 ml).This was diluted to 15 ml with diethyl ether and washed with 5% NaHCO₃(10 ml), dried over anhydrous MgSO₄, filtered off and filtrateevaporated to dryness. The residue was purified by flash columnchromatography (SiO₂, hexane, hexane/ethyl acetate 9.5:0.5) to give thetitle compound (0.024 g; 50% yield) as colourless solid. ¹H-NMR (CDCl₃)2.53 (s, 3H); 3.84 (s, 3H); 6.86 (s, 1H); 6.92 (dd, 1H, J=2.24, 8.87Hz); 7.222 (d, 1H, J=2.24 Hz); 7.51 (d, 1H, J=8.67 Hz).

Step D: 6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene

To a mixture of 6-methoxy-2-methylbenzo[b]thiophene (0.024 g; 0.132mmol) and 3,4,5-trimethoxybenzoyl chloride (0.052 g; 0.225 mmol) in1,2-dichloroethane (1 ml) SnCl₄ (0.023 ml) was added. The resultingmixture was stirred for 1 h at 40° C., quenched with H₂O (1 ml), dilutedto 15 ml with diethyl ether, washed with 5% NaHCO₃ (5 ml), brine (10ml), dried over anhydrous MgSO₄, filtered and filtrate evaporated todryness under reduced pressure. The residue was purified by flash columnchromatography (SiO₂; hexane/ethyl acetate 9:1) to give pure titlecompound (0.020 g; 41%) as a colourless crystals. ¹H-NMR (CDCl₃) 2.47(s, 3H); 3.8 (s, 6H); 3.84 (s, 3H); 3.93 (s, 3H); 6.90 (dd, 1H, J=2.4,8.89 Hz); 7.1 (s, 2H); 7.24 (d, 1H, J=2.4 Hz); 7.42 (d, 1H, J=8.89 Hz).

Example 52 Preparation of3-(3,5-Dimethoxybenzoyl)-7-hydroxy-6-methoxybenzo[b]furan

Step 1:2-t-Butyldimethylsilanyl-3-(3,5-dimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan

When 3,4,5-trimethoxyiodobenzene was replaced by3,5-di-methoxyiodobenzene as in Example 4 (step 3) the identicalprocedure afforded the title compound as a light yellow paste (102 mg,49%). ¹H NMR (300 MHz, CDCl₃) δ 7.00 (d, J=2.32 Hz, 2H), 6.81 (d, J=8.30Hz, 1H), 6.71 (d, J=8.61 Hz, 1H), 6.67 (t, J=2.31 Hz, 1H), 4.74 (m, 1H),3.86 (s, 3H, OMe), 3.78 (s, 6H, 2×OMe), 1.38 (d, 6H, J=6.16 Hz), 1.01(s, 9H), 0.27 (s, 6H).

Step 2: 3-(3,5-Dimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan

The procedure same as in Example 6 (Step 1) afforded the title compound(57 mg, 83%). ¹H NMR (300 MHz, CDCl₃) δ 8.02 (s, 1H, C₂H), 7.82 (d, 1H,J=8.59 Hz), 7.04 (d, J=8.63 Hz, 1H), 6.99 (d, J=2.31 Hz, 2H), 6.67 (t,J=2.30 Hz, 1H), 4.71 (m, 1H), 3.91 (s, 3H, OMe), 3.83 (s, 6H, 2×OMe),1.36 (d, 6H, J=6.15 Hz).

Step 3: 3-(3,5-Dimethoxybenzoyl)-7-hydroxy-6-methoxybenzo[b]furan

The procedure same as in Example 6 (Step 2) afforded the title compoundas a creamy crystalline solid (21 mg, 49%). ¹H NMR (300 MHz, CDCl₃) δ8.05 (s, 1H, C₂H), 7.69 (d, J=8.56 Hz, 1H), 7.02 (d, J=8.59 Hz, 1H),6.99 (d, J=2.03 Hz, 2H), 6.67 (broad t, 1H), 5.70 (broad s, 1H, OH),3.97 (s, 3H, OMe), 3.83 (s, 6H, 2×OMe); ¹³C NMR (75 MHz, CDCl₃) δ 189.48(CO), 160.50, 152.09, 144.56, 143.32, 140.79, 130.84, 120.87, 120.48,112.53, 109.22, 106.27, 104.28, 56.84, 55.25.

Example 53 Preparation of3-(Pentafluorobenzoyl)-6-methoxy-7-hydroxybenzo[b]furan

Step 1:2-t-Butyldimethylsilanyl-3-(pentafluorobenzoyl)-7-isopropoxy-6-methoxybenzo[b]furan

When 3,4,5-trimethoxyiodobenzene was replaced by pentafluoroiodobenzeneas in Example 4 (step 3) the identical procedure was used fornucleophilic addition, however, the oxidation step was different and wasas follow [180 mg of the crude material obtained was co-distilled withtoluene and dissolved in dry dichloromethane (5 mL) andpyridine-dichromate (266 mg, 0.71 mmol) was added to in portions and thereaction mixture was stirred for overnight (tlc). The solution wasdiluted with dichloromethane, solvent was decanted and washed withwater. The organic layer was separated, dried over magnesium sulphateand the solvent was distilled to give the crude product, which waspurified over silica gel column to afford the title compound as a lightyellow paste (156 mg, 35%)] ¹H NMR (300 MHz, CDCl₃) δ 6.82 (d, J=8.67Hz, 1H), 6.31 (d, J=8.64 Hz, 1H), 4.71 (m, 1H), 3.86 (s, 3H, OMe), 1.37(d, 6H, J=6.15 Hz), 1.03 (s, 9H), 0.42 (s, 6H).

Step 2: 3-(Pentafluorobenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan

The procedure same as in Example 6 (Step 1) afforded the title compoundas a light yellow paste (31 mg, 83%). ¹H NMR (300 MHz, CDCl₃) δ 7.89 (s,1H, C₂H), 7.83 (d, J=8.58 Hz, 1H), 7.07 (d, J=8.61 Hz, 1H), 4.69 (m,1H), 3.93 (s, 3H, OMe), 1.35 (d, 6H, J=6.16 Hz).

Step 3: 3-(Pentafluorobenzoyl)-6-methoxy-7-hydroxybenzo[b]furan

The procedure same as in Example 6 (step 2) afforded the title compoundas a creamy crystalline solid (21 mg, 63%). ¹H NMR (300 MHz, CDCl₃) δ7.93 (s, 1H, C₂H), 7.70 (d, J=8.55 Hz, 1H), 7.05 (d, J=8.56 Hz, 1H),5.73 (bs, 1H, OH), 3.98 (s, 3H, OMe).

What is claimed:
 1. A method of treating a cancer by inhibiting tubulinpolymerisation including the step of administering to a patient in needthereof a compound of formula (I)

or a salt thereof, wherein X represents O, S, SO, SO₂, Se, SeO, SeO₂ orNR where R is selected from H, O, optionally substituted acyl,optionally substituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, and optionally substituted sulfonyl; R^(1A)and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl; R^(1C) represents C₁₋₃ alkoxy, C₁₋₃alkylthio, C₁₋₃ alkylamino, or C₁₋₃ dialkylamino; R^(1D) representshydroxy, amino, or phosphate ester; L represents C═O, O, S, SO, SO₂, Se,SeO, SeO₂, C═NZ′, or NR′ where Z′ is H, optionally substituted alkyl,optionally substituted aryl or optionally substituted amino; and whereR′ is selected from H, O, optionally substituted acyl, optionallysubstituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, or optionally substituted sulfonyl;R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and Qrepresents C₁₋₄ alkyl, wherein the cancer is selected from the groupconsisting of breast cancer, renal cancer, colorectal cancer, pancreaticcancer, melanoma, skin cancer, lung cancer, mesothelioma, ovariancancer, prostate cancer, brain cancer, and leukaemia.
 2. The methodaccording to claim 1 further comprising the step of administering atleast one other cytotoxic compound.
 3. The method according to claim 1further comprising the step of administering a antihypertensive orantihypotensive agent.
 4. The method according to claim 1, wherein saidcompound is

2-methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran, or asalt thereof.
 5. The method according to claim 1 wherein said compoundis

disodium 6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-benzofuran-7-ylphosphate.
 6. A method of treating a cancer by inhibiting tubulinpolymerisation including the step of administering to a patient in needthereof a compound of formula (Ia)

or a salt thereof, wherein X represents O, S, SO, SO₂, Se, SeO, SeO₂ orNR where R is selected from H, O, optionally substituted acyl,optionally substituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, and optionally substituted sulfonyl; R^(1A)and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl; R^(1C) represents C₁₋₃ alkoxy, C₁₋₃alkylthio, C₁₋₃ alkylamino, or C₁₋₃ dialkylamino; R^(1D) representshydroxy, amino, or phosphate ester; R^(2A) and R^(2E) independentlyrepresents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro,pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo,trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl,optionally substituted acyl, optionally substituted acylamino,optionally substituted acylimino, optionally substituted acyliminoxy,optionally substituted acyloxy, optionally substituted arylalkyl,optionally substituted arylalkoxy, optionally substituted alkenyl,optionally substituted alkenyloxy, optionally substituted alkoxy,optionally substituted alkyl, optionally substituted alkynyl, optionallysubstituted alkynyloxy, optionally substituted amino, optionallysubstituted aminoacyl, optionally substituted aminoacyloxy, optionallysubstituted aminosulfonyl, optionally substituted aminothioacyl,optionally substituted aryl, optionally substituted aryloxy, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted oxyacyl, optionally substituted oxyacylamino, optionallysubstituted oxyacyloxy, optionally substituted oxyacylimino, optionallysubstituted oxysulfinylamino, optionally substituted oxysulfonylamino,optionally substituted oxythioacyl, optionally substitutedoxythioacyloxy, optionally substituted sulfinyl, optionally substitutedsulfinylamino, optionally substituted sulfonyl, optionally substitutedsulphonylamino, optionally substituted thio, optionally substitutedthioacyl, optionally substituted thioacylamino, or optionallysubstituted thioacyloxy; and Q represents C₁₋₄ alkyl, wherein the canceris selected from the group consisting of breast cancer, renal cancer,colorectal cancer, pancreatic cancer, melanoma, skin cancer, lungcancer, mesothelioma, ovarian cancer, prostate cancer, brain cancer, andleukaemia.
 7. The method according to claim 6 further comprising thestep of administering at least one other cytotoxic compound.
 8. Themethod according to claim 6 further comprising the step of administeringa antihypertensive or antihypotensive agent.
 9. A method of treating acancer by inhibiting tubulin polymerisation including the step ofadministering to a patient in need thereof a compound of formula (Ib)

or a salt thereof, wherein X represents O, S, SO, SO₂, Se, SeO, SeO₂ orNR where R is selected from H, O, optionally substituted acyl,optionally substituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, and optionally substituted sulfonyl; R^(1C)represents C₁₋₃ alkoxy; R^(1D) represents hydroxy, amino, or phosphateester; and Q represents C₁₋₄ alkyl, wherein the cancer is selected fromthe group consisting of breast cancer, renal cancer, colorectal cancer,pancreatic cancer, melanoma, skin cancer, lung cancer, mesothelioma,ovarian cancer, prostate cancer, brain cancer, and leukaemia.
 10. Themethod according to claim 9 further comprising the step of administeringat least one other cytotoxic compound.
 11. The method according to claim9 further comprising the step of administering a antihypertensive orantihypotensive agent.
 12. A method of treating a cancer by inhibitingtubulin polymerisation including the step of administering to a patientin need thereof a compound of formula (II)

or a salt thereof, wherein R^(1A) and R^(1B) each independentlyrepresents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro,pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo,trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl,optionally substituted acyl, optionally substituted acylamino,optionally substituted acylimino, optionally substituted acyliminoxy,optionally substituted acyloxy, optionally substituted arylalkyl,optionally substituted arylalkoxy, optionally substituted alkenyl,optionally substituted alkenyloxy, optionally substituted alkoxy,optionally substituted alkyl, optionally substituted alkynyl, optionallysubstituted alkynyloxy, optionally substituted amino, optionallysubstituted aminoacyl, optionally substituted aminoacyloxy, optionallysubstituted aminosulfonyl, optionally substituted aminothioacyl,optionally substituted aryl, optionally substituted aryloxy, optionallysubstituted cycloalkenyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted oxyacyl, optionally substituted oxyacylamino, optionallysubstituted oxyacyloxy, optionally substituted oxyacylimino, optionallysubstituted oxysulfinylamino, optionally substituted oxysulfonylamino,optionally substituted oxythioacyl, optionally substitutedoxythioacyloxy, optionally substituted sulfinyl, optionally substitutedsulfinylamino, optionally substituted sulfonyl, optionally substitutedsulphonylamino, optionally substituted thio, optionally substitutedthioacyl, optionally substituted thioacylamino, or R^(1A) and R^(1B)together form an optionally substituted aryl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, or optionally substituted cycloalkenyl; R^(1C) representsC₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylamino, or C₁₋₃ dialkylamino;R^(1D) represents hydroxy, amino, or phosphate ester; L represents C═O,O, S, SO, SO₂, Se, SeO, SeO₂, C═NZ′, or NR′ where Z′ is H, optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedamino; and where R′ is selected from H, O, optionally substituted acyl,optionally substituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, or optionally substituted sulfonyl;R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and Qrepresents C₁₋₄ alkyl, wherein the cancer is selected from the groupconsisting of breast cancer, renal cancer, colorectal cancer, pancreaticcancer, melanoma, skin cancer, lung cancer, mesothelioma, ovariancancer, prostate cancer, brain cancer, and leukaemia.
 13. The methodaccording to claim 12, wherein L is a carbonyl group (C═O), and at leastone of R^(2D), R^(2C) or R^(2B) is a hydroxy or C₁₋₃ alkoxy group. 14.The method according to claim 12, wherein L is a carboxyl group (C═O),and R^(2D), R^(2C), and R^(2B) are methoxy.
 15. The method according toclaim 12, wherein L is a carbonyl group (C═O), R^(2D), R^(2C), andR^(2B) are methoxy and R^(1A), R^(1B), R^(2A) and R^(2E) are H.
 16. Themethod according to claim 12, wherein L is a carbonyl group (C═O),R^(2D), R^(2C), and R^(2B) are methoxy, R^(1A), R^(1B), R^(2A) andR^(2E) are H, and R^(1D) is hydroxy.
 17. The method according to claim12 further comprising the step of administering at least one othercytotoxic compound.
 18. The method according to claim 12 furthercomprising the step of administering a antihypertensive orantihypotensive agent.
 19. A method of inhibiting tubulin polymerisationcomprising the step of administering to a patient in need thereof acompound of formula (I)

or a salt thereof, wherein X represents O, S, SO, SO₂, Se, SeO, SeO₂ orNR where R is selected from H, O, optionally substituted acyl,optionally substituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, and optionally substituted sulfonyl; R^(1A)and R^(1B) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacyloxy, optionallysubstituted oxyacylimino, optionally substituted oxysulfinylamino,optionally substituted oxysulfonylamino, optionally substitutedoxythioacyl, optionally substituted oxythioacyloxy, optionallysubstituted sulfinyl, optionally substituted sulfinylamino, optionallysubstituted sulfonyl, optionally substituted sulphonylamino, optionallysubstituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or R^(1A) and R^(1B) together form anoptionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted cycloalkenyl; R^(1C) represents C₁₋₃ alkoxy, C₁₋₃alkylthio, C₁₋₃ alkylamino, or C₁₋₃ dialkylamino; R^(1D) representshydroxy, amino, or phosphate ester; L represents C═O, O, S, SO, SO₂, Se,SeO, SeO₂, C═NZ′, or NR′ where Z′ is H, optionally substituted alkyl,optionally substituted aryl or optionally substituted amino; and whereR′ is selected from H, O, optionally substituted acyl, optionallysubstituted alkenyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, or optionally substituted sulfonyl;R^(2A)-R^(2E) each independently represents H, carboxy, cyano,dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino,phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio,trihalomethoxy, trihalomethyl, optionally substituted acyl, optionallysubstituted acylamino, optionally substituted acylimino, optionallysubstituted acyliminoxy, optionally substituted acyloxy, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted alkenyl, optionally substituted alkenyloxy, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedalkynyl, optionally substituted alkynyloxy, optionally substitutedamino, optionally substituted aminoacyl, optionally substitutedaminoacyloxy, optionally substituted aminosulfonyl, optionallysubstituted aminothioacyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted cycloalkenyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted oxyacyl, optionallysubstituted oxyacylamino, optionally substituted oxyacylimino,optionally substituted oxyacyloxy, optionally substitutedoxysulfinylamino, optionally substituted oxysulfonylamino, optionallysubstituted oxythioacyl, optionally substituted oxythioacyloxy,optionally substituted sulfinyl, optionally substituted sulfinylamino,optionally substituted sulfonyl, optionally substituted sulphonylamino,optionally substituted thio, optionally substituted thioacyl, optionallysubstituted thioacylamino, or optionally substituted thioacyloxy; or anyof R^(2A) and R^(2B), R^(2B) and R^(2C), R^(2C) and R^(2D), and R^(2D)and R^(2E), together form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted cycloalkenyl; and Qrepresents C₁₋₄ alkyl.
 20. The method according to claim 1 wherein thecancer is breast cancer.
 21. The method according to claim 1 wherein thecancer is renal cancer.
 22. The method according to claim 1 wherein thecancer is colorectal cancer.
 23. The method according to claim 1 whereinthe cancer is pancreatic cancer.
 24. The method according to claim 1wherein the cancer is melanoma.
 25. The method according to claim 1wherein the cancer is skin cancer.
 26. The method according to claim 1wherein the cancer is lung cancer.
 27. The method according to claim 1wherein the cancer is mesothelioma.
 28. The method according to claim 1wherein the cancer is ovarian cancer.
 29. The method according to claim1 wherein the cancer is prostate cancer.
 30. The method according toclaim 1 wherein the cancer is brain cancer.
 31. The method according toclaim 1 wherein the cancer is leukaemia.